Primary hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition that is caused by an abnormal accumulation of activated macrophages. The common NK- and cytotoxic T-cell dysfunction in HLH has been related to genetic defects of vesicle transport and apoptosis. Here, we identify a novel form of hereditary HLH that is related to and possibly caused by a homozygous missense mutation (G139V) of the active centre of heme oxygenase-1 (HO-1). The clinical picture of this male patient is characterized by persistent, severe microcytic hemolytic anemia without hyperbilirubinemia since birth. In the second year of life, the clinical syndrome of HLH developed with persistent fever, marked hepatosplenomegaly, thrombocytopenia, hyperferritinemia, hypertriglyceridemia, and elevated levels of soluble CD25. Liver histology showed marked lympho- and erythrophagocytosis, which confirmed the diagnosis of HLH. The clinical syndrome responded well to immunosuppressive treatment with etoposide, dexamethasone and cyclosporine A. PRF1, UNC13-D and STX11 mutations were excluded. Functional analysis of NK-activity showed only slightly decreased killing activity with normal responses of NK-cells to cytokine stimulation. Persistent endothelial damage was indicated by a pronounced elevation of vWF and D-dimer concentrations. The persistently very low bilirubin levels despite marked hemolysis suggested a defect of hemoglobin degradation. HO-1 is the rate limiting enzyme of this pathway resulting in bilirubin synthesis. Normally, HO-1 is constitutively expressed at a low level but strongly induced by heme, and hypoxia. Functional analysis of HO-1 protein in the patient’s mononuclear blood cells showed a high constitutive expression that did not respond further to heme treatment. Sequence analysis revealed a homozygous GGT (Gly) to GTT (Val) point mutation of HO-1 codon 139. This mutation of the enzyme’s active center is known from in-vitro analyses to change enzyme activity from an oxygenase into a peroxidase. Consistent with this change in activity, quantitative analysis of reactive oxygen species (ROS) metabolites in the urine of this boy showed high amounts of bilirubin oxidative metabolites, 8-hydroxy-2′-deoxyguanosine and acrolein-lysine. In this report we thus identify a novel disease entity which is characterized by an activating mutation of HO-1 which results in a defect of hemoglobin degradation, bilirubin synthesis and in excessive oxidative stress and inflammation.

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