Novel KDM6A Kabuki Syndrome Mutation With Hyperinsulinemic Hypoglycemia and Pulmonary Hypertension Requiring ECMO

Abstract

Kabuki syndrome (KS) is a multisystem disorder estimated to occur in 1:32,000 newborns. Pathogenic mutations cause the majority but not all cases of KS in either KMT2D or KDM6A . KS can be suspected by phenotypic features, including infantile hypotonia, developmental delay, dysmorphic features, congenital heart defects, and others. Still, many of these features are not readily apparent in a newborn. Although neonatal hypoglycemia has been reported in eight to ten percent of patients with KS, the incidence and severity of hyperinsulinemic hypoglycemia (HH) is not well-studied. We present a full-term female infant with HH who was responsive to low-dose Diazoxide. At three months of age, she was admitted for septic shock, worsening respiratory status and severe pulmonary hypertension, requiring extracorporeal membrane oxygenation (ECMO) support. Her neonatal history was notable for hypotonia, dysphagia with aspiration requiring gastrostomy tube placement, and a cardiac defect - hypoplastic aortic arch requiring aortic arch repair. She has characteristic facial features, including prominent eyelashes, long palpebral fissures, and a short nasal columella. Next-Generation Sequencing (NGS) for HH revealed a de novo likely pathogenic missense variant in KDM6A gene: c.3479G>T, p.Gly1160Val that was absent from population databases. Genetic testing for causes of HH should include testing of the KS genes KMT2D and KDM6A. Early detection of the underlying genetic defect will help guide management as all reported HH cases associated with KS have been responsive to Diazoxide. Affected infants with underlying cardiac conditions may be at higher risk of serious respiratory complications such as pulmonary hypertension.

Syndromic forms of congenital hyperinsulinism

“…These figures are likely to be an underestimation, as it cannot be assumed that a proper assessment for neonatal hypoglycemia and CHI was conducted for each of these patients. CHI in Kabuki syndrome has also been described in a number of case reports ( 53 – 59 ). Yap et al.…”

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

“…CEACAM1 [340], ACSL1 [341], TLR4 [342], ABCA1 [343], TLR5 [344], CYP2D6 [345], JAK2 [346], NOTCH2 [347], DDX3X [348], NCOA4 [349], EGR1 [350], IQGAP2 [351], GCLC (glutamate-cysteine ligase catalytic subunit) [352], VEGFA (vascular endothelial growth factor A) [353], ITGB1 [354], LDLR (low density lipoprotein receptor) [355], TLR6 [316], SIRT1 [356], FGL2 [357], TET2 [358], PHF2 [328], VEGFB (vascular endothelial growth factor B) [359], SELENOM (selenoprotein M) [360], TRPM4 [361], OLFM2 [362] and ATAD3A [363] are thought to be involved in non-alcoholic fatty liver disease. Altered expression of ATOH8 [364], STAT1 [365], ARG1 [366], TLR4 [367], VNN1 [368], ABCA1 [369], IFIH1 [370], PTGS2 [371], F2RL1 [289], CYP2D6 [372], PDK4 [373], RNF213 [374], JAK2 [375], NOTCH2 [376], PDGFC (platelet derived growth factor C) [377], TLR2 [378], CYP1B1 [379], IL1RN [380], GCH1 [381], EGR1 [382], HIF1A [383], PLA2G7 [384], CCR2 [385], GAB1 [386], VEGFA (vascular endothelial growth factor A) [387], OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) [388], OXR1 [389], IRF9 [390], FMR1 [391], LDLR (low density lipoprotein receptor) [392], SIRT1 [393], NOD2 [394], ATP13A3 [395], VCAN (versican) [396], FGL2 [397], TET2 [398], KDM6A [399], KLHL2 [400], CAVIN1 [401], TNFRSF4 [402], PF4 [403], VEGFB (vascular endothelial growth factor B) [330], CCR7 [404], PRDX2 [405], HSPB1 [406], TCF4 […”

Persistent Hypoglycemia and Hyperinsulinism in a Patient With KMT2D-Associated Kabuki Syndrome

“…Hyperinsulinism in the neonate may present as an isolated finding or manifest in various genetic syndromes [ 1 ]. KS is a more recent addition to the list of genetic syndromes associated with HH [ 4 ]. KS is classically caused by a pathogenic mutation in either the KMT2D or KDM6A gene.…”

“…KS is classically caused by a pathogenic mutation in either the KMT2D or KDM6A gene. Heterozygous mutations in the KMT2D gene are responsible for more than 75% of KS, with most being de novo [ 4 ]. Almost 30% of patients with clinical features of KS do not carry mutations in either gene, and other genes have been associated with Kabuki-like phenotypes [ 5 ].…”