Familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis or primary hemophagocytic lymphohistiocytosis, is a rare and life-threatening inherited disorder of the immune system. It belongs to a group of conditions called hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled activation and proliferation of T lymphocytes and macrophages that infiltrate multiple organs. This excessive immune activation leads to widespread tissue damage and organ dysfunction. The disease primarily affects the hematologic, hepatic, neurological, and immune systems. Key clinical features include prolonged high fever, enlarged liver and spleen (hepatosplenomegaly), cytopenias (low blood cell counts affecting red blood cells, white blood cells, and platelets), elevated ferritin and triglycerides, low fibrinogen, and evidence of hemophagocytosis (macrophages engulfing blood cells) in the bone marrow, spleen, or lymph nodes. Neurological involvement is common and may include irritability, seizures, cranial nerve palsies, ataxia, and altered consciousness. Liver dysfunction with jaundice and coagulopathy may also occur. Without treatment, the disease is rapidly fatal. Several genetic subtypes have been identified: FHL type 2 (PRF1 gene), FHL type 3 (UNC13D gene), FHL type 4 (STX11 gene), and FHL type 5 (STXBP2 gene). These genes encode proteins essential for the cytotoxic function of natural killer cells and cytotoxic T lymphocytes. Treatment involves immunosuppressive and chemotherapeutic protocols, most commonly the HLH-94 or HLH-2004 protocols, which include dexamethasone, etoposide, and cyclosporine A. Intrathecal methotrexate may be used for central nervous system involvement. However, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT), which is recommended for all patients with confirmed familial forms of the disease.

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