A Novel De Novo KMT2D Genetic Variant in Kabuki Syndrome: A Case Report

IntroductionKabuki syndrome (KS) is a rare, complex, multisystem, neurodevelopmental congenital disorder with characteristic phenotypic anomalies and pathogenic genetic variants of the KMT2D or KDM6A genes. KS is highly associated with dysregulation of terminal B cell differentiation, frequently leading to humoral immune deficiency and immunodysregulation. We present a novel heterozygous, de novo, pathogenic variant of KMT2D, c.6761del (p.N2254Tfs*10), identified on clinical trio whole-exome sequencing (WES) in a 7-month-old male with a recent KS diagnosis.Case PresentationA 7-month-old male, born prematurely at 33 weeks gestation, requiring prolonged neonatal intensive care unit (NICU) stay, with complex cardiac history including pulmonary atresia, ventricular septal defect status post-patent ductus arteriosus stenting, and pulmonary hypertension, initially admitted 3 months prior for management of severely excoriated diaper dermatitis, transferred to the pediatric cardiac ICU since, for chronic hypoxemic respiratory failure necessitating recent tracheostomy placement and mechanical ventilation, with recurrent bacterial tracheitis. He had been on dual antibiotic therapy for the management of persistent Serratia marcescens and Pseudomonas aeruginosa tracheitis and pneumonia. WES showed a pathogenic heterozygous KMT2D variant associated with KS, prompting a immunology consultation. Initial immune evaluation identified hypogammaglobulinemia, with serum IgG 127 mg/dL, mildly elevated IgA 67 mg/dL, and normal IgM 91 mg/DL. Intravenous immunoglobulin was initiated at 500 mg/kg every 4 weeks, with plans for close outpatient monitoring.DiscussionKS is a rare, multisystem congenital neurodevelopmental disorder typically diagnosed between 3 and 12 years old, when its craniofacial anomalies become more recognizable. Our patient’s prolonged hospitalization for management of complex congenital heart disease, chronic respiratory failure, and recurrent bacterial infections prompted inpatient genetics evaluation, which revealed KS with a novel KMT2D pathogenic variant. Our patient’s hypogammaglobulinemia is a common humoral immune defect among patients with KS. His history of complex cardiopulmonary disease and recurrent bacterial infections prompted early genetics evaluation, with the identification of a novel variant associated with KS and prompt initiation of immunoglobulin replacement therapy for hypogammaglobulinemia. Initial and serial clinical immune evaluations are advised for all patients with known KS to offer early intervention and prevent sequela.