A Fatal Course of Hemophagocytic Lymphohistiocytosis in a Child with Homozygous ERCC6L2 Defect and Heterozygous ADA2 Variant: A Case Report

Szymon Lulek¹Katarzyna Bąbol-Pokora²Monika Radwańska³Daniel Popiel³Magdalena Reich¹Wojciech Mlynarski²Radoslaw Chaber^1*

• ¹University of Rzeszow, Rzeszów, Poland
• ²Uniwersytet Medyczny w Lodzi, Łódź, Poland
• ³Szpital Wojewodzki Nr 2 im Sw Jadwigi Krolowej w Rzeszowie, Rzeszow, Poland

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 ERCC6L2, 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 ERCC6L2 and a heterozygous ADA2 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 ERCC6L2 variant. The co-occurrence of a heterozygous ADA2 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. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may arise secondary to genetic or environmental triggers. While HLH has been described in association with ADA2 deficiency, it has not yet been reported in the context of ERCC6L2-related bone marrow failure. We present a fatal case of HLH in a 2-year-old girl with persistent fever, cytopenias, hepatosplenomegaly, liver failure, and multiorgan dysfunction. Despite HLH-directed therapy, the disease progressed rapidly. Genetic testing revealed a homozygous pathogenic variant in ERCC6L2 and a heterozygous variant in ADA2, suggesting a combined predisposition to immune dysregulation and marrow failure. This is the first reported case of HLH associated with ERCC6L2 deficiency. The co-occurrence of an ADA2 variant may have amplified the inflammatory response. Our findings highlight the importance of genetic evaluation in pediatric HLH, especially in the presence of cytopenias or severe infection history, and expand the spectrum of genetic conditions linked to HLH.