Hemophagocytic Lymphohistiocytosis Triggered by Influenza B in a Child with ARFGEF2 mutation

Introduction

Mutations in the ARFGEF2 gene (ADP-ribosylation factor guanine nucleotide-exchange factor 2), a crucial regulator of intracellular vesicular trafficking, have been associated with multisystemic disorders. These include well-characterized neurodevelopmental abnormalities such as microcephaly, periventricular nodular heterotopia, refractory epilepsy, and dystonic movement disorders, as well as non-neurological features like restrictive cardiomyopathy (Sheen VL et al., Nat Genet 2004; 36: 69–76, Radhakrishna H et al., J Cell Biol 1997; 139: 49–61). The underlying pathophysiological mechanism involves impaired vesicle formation and trafficking, particularly at the Golgi apparatus, leading to dysregulated neuronal proliferation and migration, as well as compromised cardiac muscle architecture and function (Sheen VL et al., Nat Genet 2004; 36: 69–76). However, literature on the immune consequences of ARFGEF2 mutations is sparse, and a mechanistic link to immune dysregulation remains largely unexplored. These mutations may also influence immune function, potentially predisposing affected individuals to hyperinflammatory responses such as hemophagocytic lymphohistiocytosis (HLH).

HLH, is characterized by an overwhelming hyperinflammatory response driven by excessive activation of T lymphocytes and macrophages. Diagnostic features include persistent fever, hepatosplenomegaly, cytopenias affecting≥2 lineages, hypertriglyceridemia, hyperferritinemia, hypofibrinogenemia, and hemophagocytosis in bone marrow or other tissues, as defined by the HLH-2004 criteria (Henter JI et al., Pediatr Blood Cancer 2007; 48 (2): 124–31). Although HLH may occur in autoimmune conditions and malignancies, viral infections–particularly influenza–are recognized as potent triggers, especially in individuals with underlying immunologic or genetic susceptibilities (Grom AA et al., Nat Rev Rheumatol 2016; 12: 259–268). Influenza B has immunomodulatory properties capable of disrupting cytokine regulation and promoting hemophagocytic responses (Grom AA et al., Nat Rev Rheumatol 2016; 12: 259–268, Lee JS et al., Sci Immunol 2020; 5: eabd1554).

Here, we report a rare and fatal case of HLH in a 4-year-old boy with a genetically confirmed ARFGEF2 mutation following influenza B infection. This case underscores the complex interplay between genetic background and infectious triggers in the manifestation of HLH.

Publication History

Article published online:
10 September 2025