Long term follow-up of multiorgan disease in Kleefstra syndrome 2 in an adult - case report.

Objectives: The Kleefstra syndrome spectrum (KSS) is a group of neurodevelopmental disorders characterized by intellectual disability, behavioral disorders, growth and neurodevelopmental delay, facial dysmorphism and neurological deficits. Kleefstra syndrome 2 (KLEFS2) is a part of KSS and is due to heterozygous loss-of-function variants in the KMT2 C gene. We report the long-term clinical course and multi-organ manifestations of a patient with KLEFS2 caused by a novel heterozygous pathogenic variant in KMT2 C.

Methods: A patient with KSS phenotype developed proteinuria with progressive kidney dysfunction secondary to focal segmental glomerular sclerosis. She subsequently developed recurrent episodes that mimicked mitochondrial stroke-like episodes. The phenotype included encephalopathy, stroke-like episodes with focal status epilepticus with impaired consciousness associated with cortical and subcortical T2/FLAIR signal hyperintensities that partially responded to intravenous arginine infusions.

Results: Exome sequencing revealed a heterozygous pathogenic nonsense variant in KMT2 C (NM_170606.3) c.3940C > T (p.Gln1314Ter). Nuclear and mitochondrial DNA variants associated with mitochondrial disorders have been excluded.

Discussion: This is a case of KLEFS2 with longitudinal 10 year follow up and its previously unreported multi-organ clinical manifestations including stroke-like episodes and nephrotic disease. Our report further expands the phenotypic spectrum of KLEFS2. Further reports of patients with KLEFS2 with multi-organ involvement should be sought to confirm our findings.