A fatal course of hemophagocytic lymphohistiocytosis in a child with homozygous ERCC6L2 defect and heterozygous ADA2 variant: a case report

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may arise secondary to genetic or acquired triggers. Although HLH has been reported in patients with adenosine deaminase 2 (ADA2) deficiency, to date it has not been reported in individuals harboring pathogenic variants in <i>ERCC6L2</i>, a gene typically linked to inherited bone marrow failure. We report a fatal case of HLH in a 2-year-old girl with persistent fever, cytopenias, hepatosplenomegaly, liver failure, and multiorgan dysfunction. Despite targeted HLH therapy, the disease progressed rapidly. Genetic testing identified a homozygous pathogenic variant in <i>ERCC6L2</i> and a heterozygous <i>ADA2</i> variant, which we interpret as indicating a susceptibility background to immune dysregulation, with HLH most plausibly occurring as a secondary, trigger-dependent event. No functional validation was performed, and causal inference cannot be made on this basis. To our knowledge, this is the first documented case of HLH in a patient with a homozygous pathogenic <i>ERCC6L2</i> variant. The co-occurrence of a heterozygous <i>ADA2</i> variant may have modulated the hyperinflammatory response. These observations highlight the importance of genetic evaluation and suggest-while not proving-a broader spectrum of genetic contexts associated with pediatric HLH; confirmation will require functional studies and replication.