Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency

Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome associated with mutations in genes required for lymphocyte cytotoxicity. Our aim was to describe the clinical, genetic and immunological characteristics of two unrelated patients with congenital IFN-γ receptor-deficiency who initially presented with HLH. The molecular defect was identified by whole exome sequencing and direct sequencing of candidate genes. Flow cytometry and functional assays were used for immunological profiling. We described a 2-month old infant and a 4-year old child first diagnosed with fulminant HLH. Only later were disseminated Mycobacterium bovis following BCG vaccination and Mycobacterium tuberculosis infection found in the respective patients. Genetic analyses identified homozygous IFNGR2 deletions in the 2-month old patient and homozygous missense IFNGR1 mutations in the 4-year old patient, whereas no mutations were identified in genes required for lymphocyte cytotoxicity. In one patient, cellular analyses confirmed defective IFN-γ-mediated STAT1 phosphorylation, consistent with a diagnosis of complete IFN-γR2 deficiency and Mendelian susceptibility to mycobacterial disease (MSMD). Interestingly, a paucity of peripheral blood NK cells was noted in both patients and NK cell activity was defective in the one tested. Our findings of HLH in two patients with IFN-γ receptor-deficiency highlight the importance of IFN-γ-independent pathological mechanisms for HLH, revealing connections between HLH and MSMD and demonstrating the efficacy of refined functional assays in the clinical diagnosis of HLH. Moreover, our results may expand the spectrum of genes associated with HLH susceptibility, providing further mechanistic insights. Clinical implications: 1)HLH can manifest in individuals with genetically impaired IFN-γ signaling. Anti-IFN-γ antibody therapy may not be effective for management of HLH in such patients. 2)Fatal HLH can develop in IFN-γ receptor-deficiency, revealing connections between HLH and MSMD, demonstrating the efficacy of refined functional assays for stratification of primary HLH, and highlighting the importance of IFN-γ-independent mechanisms of disease pathogenesis.