Familial haemophagocytic lymphohistiocytosis: advances in the genetic basis, diagnosis and management

Abstract

SummaryFamilial haemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder of immune dysregulation associated with uncontrolled T cell and macrophage activation and hypercytokinaemia. The incidence of FHL is 0·12/100·000 children born per year, with a male to female ratio of 1:1. The disease is classified into six different types based on genetic linkage analysis and chromosomal localization; five specific genetic defects have been identified, which account for approximately 90% of all patients. Type 1 is due to an as yet unidentified gene defect located on chromosome nine. Type 2 is caused by mutations in the perforin (PRF1) gene, type 3 by mutations in the Munc-13-4 (UNC13D) gene, type 4 by mutations in the syntaxin 11 (STX11) gene and the recently described type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2). The incidence of the five types varies in different ethnic groups. The most common presenting features are pyrexia of unknown origin, pronounced hepatosplenomegaly and cytopenias. Neurological features tend to present later and are associated with poor prognosis. Absent or decreased lymphocyte cytotoxicity is the cellular hallmark of FHL. Biochemical features such as hyperferritinaemia, hypertriglyceridaemia and hypofibrinogenaemia are usually present, along with high levels of soluble interleukin 2 receptor in the blood and cerebrospinal fluid. Bone marrow aspirate may demonstrate the characteristic haemophagocytes, but initially is non-diagnostic in two-thirds of patients. Established international clinical, haematological and biochemical criteria now facilitate accurate clinical diagnosis. The disease is fatal unless a haematopoietic stem cell transplant (HSCT) is performed. The introduction of HSCT has dramatically improved the prognosis of the disease. However, the mortality of the disease is still significantly high and a number of challenges remain to be addressed. Active disease at the time of the transplant is the major significant poor prognostic factor. Delayed diagnosis, after irreversible organ damage has occurred, especially neurological damage, disease reoccurrence and pre-transplant mortality, remain a concern.

Between a rock and a hard place

“…The syndrome was originally described as a hereditary autosomal recessive disorder affecting infants with an incidence of < 1-1.2/100,000 births (familial HLH). The mutations identified to date lead to abnormalities in the perforin cytotoxic pathway causing decreased function of NK-and/or cTC, indicating a pivotal role of this event in the pathogenesis of HLH [2]. Recently, there have been increasing reports of adult onset HLH in the context of conditions associated with immune dysregulation: hematologic malignancies, infections, autoimmune diseases, organ/ stem cell transplants and chemo-or immunosuppressive therapies [3][4][5][6][7].…”

Hemophagocyte Lymphohistiocytosis Secondary to Bilateral Epididymal Diffuse Large B-Cell Lymphoma

“…Based on the pathogenesis of HLH, the syndrome can be classified as inherited or acquired. The former usually arises in infants and has been attributed to defects in the perforin function of the cytolytic granules of NK cells and cytotoxic T lymphocytes [1]. The acquired forms of HLH have been associated with infections, inflammatory diseases and malignancies.…”

Mutation of FAS, XIAP, and UNC13D Genes in a Patient With a Complex Lymphoproliferative Phenotype

“…On the basis of characteristics described above, upon receiving informed consent from the parents we sequenced the following genes: FAS and CASP10; PRF1, UNC13D, and STX11; and SH2D1A and XIAP, which are involved in ALPS, 1,2 FHL, 3 and XLP disease, 5 respectively. Additionally, we typed the variations in the OPN gene, which have been found to be predisposing factors for ALPS development.…”

“…1,2 FHL is a result of defective perforin-mediated cytotoxicity, leading to ineffective immune hyperactivation upon viral infection, with tissue damage and a fatal outcome. 3 XLP disease is attributed to defective function of Slam-associated protein (SAP), a natural killer (NK)-cell costimulator, causing increased susceptibility to Epstein-Barr virus infection. 4 However, 1 known XLP variant is due to defective function of the X-linked inhibitor of apoptosis protein (xiap).…”