Rare diseases presenting with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory disorder characterized by hypercytokinemia caused by excessive activation of cytotoxic T cells and macrophages. HLH is caused by a variety of factors and is classified into primary and secondary HLH. Familial HLH (FHL) types 1-5, X-linked lymphoproliferative syndrome types 1 and 2, and FHL syndrome with hypopigmentation are all examples of primary HLH. Secondary HLH, on the other hand, is linked to infections, malignant tumors, autoimmune diseases, and other diseases. The causes of HLH vary, and finding the underlying disease is critical for diagnosis and treatment. The majority of HLH is caused by the aforementioned conditions; however, approximately 10% of cases are caused by rare diseases such as inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Novel IEI, such as RhoG, MAP kinase activating death domain, TIM3, and ZNFX1 deficiencies, have recently been identified as causes of HLH. IEM patients are rarely associated with HLH. Surprisingly, children with lysinuric protein intolerance and lysosomal acid lipase deficiency (Wolman disease) frequently develop HLH. This review focuses on the most recent knowledge of HLH caused by rare diseases such as IEI and IEM.