Familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a form of histiocytosi s syndrome which has shown autosomal recessive inheritance and usually occu rs in infancy. Although the incidence of FHL is one in 50,000 to 76,000 liv e births, it is difficult to distinguish FHL from other disorders if the pa tient is a first child or has no affected siblings. Several genetic factors such as a high parental consanguinity and segregation ratio support autoso mal recessive form of inheritance in FHL. The clinical findings of FHL are usually non-specific; a high incidence of fever and splenomegaly followed b y hepatomegaly, lymphadenopathy, rash and jaundice. Neurological abnormalit ies are also present in some patients. The laboratory findings include cyto penia (anemia and thrombocytopenia), liver dysfunction, hypofibrinogenemia and hyperlipidemia. Atypical lymphoid cells are observed in some patients a t diagnosis. Since hemophagocytosis in bone marrow is detected in only half of the patients, an absence of hemophagocytosis does not exclude the diagn osis of FHL. Several cytokines have become biological markers of the active state of FHL, which include tumor necrosis factor (TNF), interleukin (IL)- 6, interferon(IFN)-gamma, and soluble IL-2 receptor. Impaired natural kille r (NK) cell activity has been found in the majority of cases. It is now acc epted that FHL is a disorder of T-cell fuction. We recently confirmed the c lonality of the specific V beta-J beta fragment of T cells in 4 of 5 FHL pa tients. The association of these clonal T-cell subpopulations and the patho genesis of FHL remains an unresolved issue. Though the role of viral infect ion in FHL is controversial, some viral infections may elicit a bout of FHL in genetically predisposed individuals. We analyzed the clonality of T cel ls in patients have Epstein-Barr virus (EBV) infection; different clonal T- cell subsets were induced in patients at progression when the activation of EBV was observed, suggesting that the EBV was in part associated with the progression of the FHL. Even with intensive therapy including VP16 and immu nosuppressive drugs, the prognosis of FHL remains fatal. The only accepted curative therapy of FHL is allogeneic bone marrow transplantation (BMT). In a patient who has no HLA-matched sibling, other stem cell transplantations such as unrelated BMT or cord blood transplantation should be considered. However, the related donor must be evaluated carefully, because of the lack of laboratory criteria that can prove the absence of the disease in the do nor. In the future, the identification of the genetic defect underlying the disorder will provide the foundation for developing the best strategy for the treatment and carrier detection of FHL.