Case Report: From intellectual disability to fatal cytokine storm: long-term follow-up reveals a novel systemic phenotype in METTL23-related disorder
- 1Department of Pediatric Intensive Care Unit, Jiangxi Provincial Children’s Hospital, Nanchang, China
- 2Department of Neurology, Jiangxi Provincial Children’s Hospital, Nanchang, China
Abstract
METTL23 is a rare gene encoding a lysine/arginine methyltransferase associated with autosomal recessive intellectual disability 44 (MIM 615942). To date, published cases have been limited to neurodevelopmental phenotypes, with recent mechanistic work also implicating METTL23 in histone H3R17 methylation and negative regulation of NF-κB–mediated proinflammatory signaling. We previously reported the neurodevelopmental phenotype of a Chinese girl with a novel homozygous METTL23 splice variant (c.322 + 1del). Here we report the long-term follow-up and fatal outcome of the same patient. Over a 3-year follow-up period, the patient experienced three episodes of autoimmune hemolytic anemia and a secundum atrial septal defect treated by percutaneous closure. At 4 years and 6 months, she was admitted with fever and cyanosis progressing to Epstein–Barr virus-associated cytokine storm with features overlapping, but not fulfilling, HLH-2004 criteria; the episode was managed clinically as septic multi-organ dysfunction. The illness was complicated by acute kidney injury requiring three sessions of continuous renal replacement therapy, myocarditis, and methicillin-resistant Staphylococcus aureus superinfection. Despite intensive multidisciplinary treatment, the illness progressed to multifocal intracranial hemorrhage with herniation, and the family elected to discontinue care; the patient died shortly thereafter. This case extends the phenotypic spectrum of METTL23-related disorder beyond neurodevelopmental impairment to include recurrent autoimmune cytopenia and a fatal virus-triggered cytokine storm. Given the reported role of METTL23 in restraining NF-κB–driven cytokine production, we hypothesize that loss-of-function variants may confer susceptibility to dysregulated inflammatory responses upon viral triggers, independent of whether formal HLH criteria are met. Long-term multidisciplinary surveillance, including vigilance for infection-triggered hyperinflammation, may be warranted in patients with METTL23-related disorder.
Related
- Case Report: A novel hemizygous nonsense variant in PPP1R3F gene associated with developmental delay, intellectual disability and autism spectrum disorder
- Microduplication of the ARID1A gene causes intellectual disability with recognizable syndromic features
- The Role of the Immunoglobulin Superfamily of Cell Adhesion Molecules in Intellectual Disability
- Reduction of forebrain interneurons alters cellular organization and cortical neurogenesis in a mouse model of X-linked intellectual disability
- Hyperphosphatasia With Intellectual Disability (Mabry Syndrome) due to Compound Heterozygous PIGO Variants: First Molecularly Characterized Case in French Guiana: A Case Report and Review of the Literature.
BibTeX
@article{zhan2026case,
title = {{Case Report: From intellectual disability to fatal cytokine storm: long-term follow-up reveals a novel systemic phenotype in METTL23-related disorder}},
author = {Yishan Zhan and Jian Zha and Hui Chen and Yuanyuan Chen},
journal = {Frontiers in Pediatrics},
year = {2026},
month = oct,
doi = {10.3389/fped.2026.1991266},
url = {https://doi.org/10.3389/fped.2026.1991266},
note = {CC BY},
}
RIS
TY - JOUR
TI - Case Report: From intellectual disability to fatal cytokine storm: long-term follow-up reveals a novel systemic phenotype in METTL23-related disorder
AU - Yishan Zhan
AU - Jian Zha
AU - Hui Chen
AU - Yuanyuan Chen
PY - 2026
DA - 2026/10/26
JO - Frontiers in Pediatrics
DO - 10.3389/fped.2026.1991266
UR - https://doi.org/10.3389/fped.2026.1991266
AB - METTL23 is a rare gene encoding a lysine/arginine methyltransferase associated with autosomal recessive intellectual disability 44 (MIM 615942). To date, published cases have been limited to neurodevelopmental phenotypes, with recent mechanistic work also implicating METTL23 in histone H3R17 methylation and negative regulation of NF-κB–mediated proinflammatory signaling. We previously reported the neurodevelopmental phenotype of a Chinese girl with a novel homozygous METTL23 splice variant (c.322 + 1del). Here we report the long-term follow-up and fatal outcome of the same patient. Over a 3-year follow-up period, the patient experienced three episodes of autoimmune hemolytic anemia and a secundum atrial septal defect treated by percutaneous closure. At 4 years and 6 months, she was admitted with fever and cyanosis progressing to Epstein–Barr virus-associated cytokine storm with features overlapping, but not fulfilling, HLH-2004 criteria; the episode was managed clinically as septic multi-organ dysfunction. The illness was complicated by acute kidney injury requiring three sessions of continuous renal replacement therapy, myocarditis, and methicillin-resistant Staphylococcus aureus superinfection. Despite intensive multidisciplinary treatment, the illness progressed to multifocal intracranial hemorrhage with herniation, and the family elected to discontinue care; the patient died shortly thereafter. This case extends the phenotypic spectrum of METTL23-related disorder beyond neurodevelopmental impairment to include recurrent autoimmune cytopenia and a fatal virus-triggered cytokine storm. Given the reported role of METTL23 in restraining NF-κB–driven cytokine production, we hypothesize that loss-of-function variants may confer susceptibility to dysregulated inflammatory responses upon viral triggers, independent of whether formal HLH criteria are met. Long-term multidisciplinary surveillance, including vigilance for infection-triggered hyperinflammation, may be warranted in patients with METTL23-related disorder.
SN - 2296-2360
ER -