title: Hemophagocytic lymphohistiocytosis and related disorders.
abstract: OBJECTIVE
  The rate of diagnosis of hemophagocytic lymphohistiocytosis, a genetically heterogeneous and, frequently, rapidly fatal autosomal recessive disorder of immune regulation, is increasing worldwide. Awareness has grown through the Histiocyte Society and the publication of newly-recognized genetic causes. I summarize current knowledge regarding the pathophysiology, diagnosis and treatment of hemophagocytic lymphohistiocytosis.
  
  
  RESULTS
  Genetic defects leading to life-threatening hemophagocytic syndromes have recently been described. Two autosomal recessive gene defects underlie 40-50% of primary (familial) cases worldwide: perforin, the major immune cytotoxic protein, and MUNC 13-4, a protein involved in exocytosis of perforin-bearing cytotoxic granules during apoptosis. Related autosomal recessive defects of secretory cytotoxic lysosomes - LYST 1 (Chediak-Higashi syndrome), Rab27A (Griscelli syndrome), and X-linked lymphoproliferative disorder - also carry a very high risk of fatal hemophagocytic lymphohistiocytosis. Concurrently, treatment protocols involving multiagent immunomodulatory therapy followed by allogeneic hematopoeitic cell transplantation have been tested. With immunomodulatory treatment, 75% of children with hemophagocytic lymphohistiocytosis are symptomatically improved after 2 months of therapy. Disease-free survival after allogeneic hematopoeitic cell transplantation currently ranges from 50 to 70%.
  
  
  CONCLUSIONS
  Bench and clinical research have advanced understanding of the pathophysiology of hemophagocytic lymphohistiocytosis and related disorders, and significantly improved clinical outcomes during the past decade.
authors.affiliation: Cincinnati Children's Hospital Medical Center, ML 7015, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. lisa.filipovich@cchmc.org
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Filipovich
mesh_terms: D002985:Clinical Protocols; D003937:Diagnosis, Differential; D018572:Disease-Free Survival; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D015996:Survival Rate; D014184:Transplantation, Homologous; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000276:immunology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000276:immunology; D000075745:rab27 GTP-Binding Proteins
chemical_list: C102161:LYST protein, human; D008565:Membrane Proteins; C507969:UNC13D protein, human; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins