Case Report: From intellectual disability to fatal cytokine storm: long-term follow-up reveals a novel systemic phenotype in METTL23-related disorder

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- κ B–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- κ B–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.