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

TL;DR

This case report describes a 10-year follow-up of a patient with Kleefstra syndrome 2, highlighting new multi-organ complications like kidney disease and stroke-like episodes.

Contribution

The report presents previously unreported multi-organ manifestations in Kleefstra syndrome 2, expanding its known clinical spectrum.

Findings

The patient developed focal segmental glomerular sclerosis and proteinuria over time.

Stroke-like episodes with neurological symptoms partially responded to arginine infusions.

A novel pathogenic variant in the KMT2C gene was identified through exome sequencing.

Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s12883-025-04210-8.

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