Familial hemophagocytic lymphohistiocytosis

Zur Stadt et al. (2005) summarized the clinical features of hemophagocytic lymphohistiocytosis (HLH), a rare autosomal recessive disorder characterized by massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently central nervous system involvement. In FHL, the familial form of the disease, first episodes occur mostly during infancy, with a rapidly fatal outcome if untreated. Diagnostic criteria also include low fibrinogen and high triglyceride and ferritin levels. Chemoimmunotherapy based on corticosteroids, epipodophyllotoxins, and cyclosporin succeeds in controlling the disease in the majority of patients, although remission is rarely obtained (Henter et al., 2002). Most patients suffer an early death unless they are treated by hematopoietic stem cell transplantation (Durken et al., 1999). Genetic Heterogeneity of Familial Hemophagocytic Lymphohistiocytosis Familial hemophagocytic lymphohistiocytosis (FHL1) has been mapped to chromosome 9q. Also see FHL2 (603553), caused by mutation in the PRF1 gene (170280) on chromosome 10q22; FHL3 (608898), caused by mutation in the UNC13D gene (608897) on chromosome 17q25; FHL4 (603552), caused by mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24; and FHL5 (613101), caused by mutation in syntaxin-binding protein-2 (STXBP2; 601717), which is an interaction partner of STX11, on chromosome 19p13. Before the identification of mutations in the RAG1 (179615) and RAG2 (179616) genes, both of which map to 11p, Omenn syndrome (familial reticuloendotheliosis with eosinophilia; 603554) was not thought to be clearly distinct from other reported cases of hemophagocytic lymphohistiocytosis. Mutation in the HAVCR2 gene (606652) on chromosome 5q23 causes an inflammatory disorder that is sometimes associated with HLH (SPTCL; 618398). Mutation in the RC3H1 gene (609424) on chromosome 1q25 causes a hyperinflammatory disorder with HLH-like features (IMDYSHI; 618998).

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