Comparative meta‐analysis of Kabuki syndrome with and without hyperinsulinaemic hypoglycaemia

Abstract

Background and ObjectiveKabuki syndrome (KS), caused by pathogenic variants in KMT2D or KDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%‐4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta‐analysis.MethodsData of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics.ResultsSeven new patients were identified with seven different pathogenic variants in KDM6A (n = 4) or KMT2D (n = 3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta‐analysis, 24 KS patients with HH had a significantly higher frequency of variants in KDM6A compared to 373 KS patients without HH (50% vs 11.5%, P < .001), and KDM6A‐KS was more likely to be associated with HH than KMT2D‐KS (21.8% vs. 3.5%, P < .001). Sex distribution and other phenotypic features did not differ between KS with and without HH.ConclusionThe higher incidence of HH in KDM6A‐KS compared to KMT2D‐KS indicates that KDM6A loss of function variants predispose more specifically to beta cell dysfunction compared to KMT2D variants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.

Neonatal hyperinsulinemic hypoglycemia: case report of kabuki syndrome due to a novel KMT2D splicing-site mutation

“…Aberrations of the mitogen-activated protein kinase (MAPK) signaling pathway in zebrafish morphants for kmt2d and rap1, as well as Kmt2d knock out mices have also been reported [20]. A lower incidence of hypoglycemia in KMT2D compared to KDM6A variants, respectively 3.5 and 21.8% has been recently reported [25]. In our patient persistent hypoglycemia represented the main neonatal emergency.…”

“…Diazoxide, the first-line pharmacologic treatment is, a potassium channel agonist that binds to the sulfonylurea receptor component of the beta cell's KATP channel, resulting in hyperpolarization of the plasma membrane and cessation of insulin secretion [26]. No differences were observed in the responsiveness to diazoxide effect between KMT2D and KDM6A variants [25]. It is administered orally with gradual dose titration up to 10-15 mg/kg/day divided 3 times daily [27].…”

Open-Source Technology for Real-Time Continuous Glucose Monitoring in the Neonatal Intensive Care Unit: Case Study in a Neonate With Transient Congenital Hyperinsulinism (Preprint)

“…Genetic testing did not reveal any disease-relevant pathologic variation in genes that are most frequently associated with CHI: ABCC8 (GenBank NM_000352.4), HADH (GenBank NM_005327.4), HNF4A (GenBank NM_175914.4), KCNJ11 (GenBank NM_000525.3), and UCP2 (NM_003355.2). However, we detected a novel, highly conserved, and heterozygous missense variant in the KMT2D gene (c.3976C>T, R1326W), which was interpreted as a pathogenic variant within this analysis and might be causative in this particular case of a Kabuki syndrome with predominantly transient, congenital hyperinsulinism [17,18].…”

Hyperinsulinemic Hypoglycemia in Three Generations of a Family with Glucokinase Activating Mutation, c.295T>C (p.Trp99Arg)

“…The genetic background of the remaining cases is unknown. Other systemic diseases such as Kabuki, Rubinstein-Taybi, Sotos, Beckwith-Wiedemann, Costello and Turner syndrome can present with hyperinsulinemic hypoglycemia as a major symptom [2]. Depending on which locus bears a pathogenic mutation, the disease-associated loci differ in phenotype and pattern of inheritance.…”