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Review
, 163 (3), 271-83

Familial Haemophagocytic Lymphohistiocytosis: Advances in the Genetic Basis, Diagnosis and Management

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Review

Familial Haemophagocytic Lymphohistiocytosis: Advances in the Genetic Basis, Diagnosis and Management

C Gholam et al. Clin Exp Immunol.

Abstract

Familial 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.

Figures

Fig. 1
Fig. 1
Model of the molecular mechanisms of familial haemophagocytic lymphohistiocytosis. Following cytotoxic T cell activation and the formation of the immunological synapse with the target cell, the microtubule organizing centre (MTOC) moves to the contact site repolarizing the microtubule network. Lytic granules move along the microtubules towards the contact site and they dock to the plasma membrane. Priming and fusion with the membrane follows and the contents of the lytic granules, i.e. perforin and granzymes, are released into the intercellular space, causing rapid death of the target cell. Defects in trafficking [?lysosomal trafficking regulator (LYST)], docking (Rab27a), priming (Munc13-4) fusion [syntaxin (STX)11 and STXB2 or Munc18-2) and target cell entry (perforin) all result in different types of the disease which are indicated. The precise mechanisms and other effectors involved in the process remain to be elucidated.
Fig. 2
Fig. 2
Fluorescence activated cell sorter (FACS) base diagnosis of X-linked lymphoproliferative disease (XLP) and familial haemophagocytic lymphohistiocytosis (FHL)2. FACS plots on the left are gated on natural killer (NK) cells and show a normal individual on top and two individuals with confirmed perforin mutations below. FACS plots of the right gated on CD8+ T cells show a normal individual on top and two confirmed XLP patients below. Mutations are indicated in each plot.
Fig. 3
Fig. 3
Granule release assay used to screen patients for familial haemophagocytic lymphohistiocytosis (FHL)3 and FHL4. (a) Granule release assay of CD8+ T cells unstimulated or stimulated with anti-CD3. The normal individual is on the left, FHL3 patient in the middle and FHL4 patient is on the right. Mutations are indicated on the plots. (b) Immunoblot showing absent Munc13-4 in a FHL3 patient (P) and normal Munc13-4 expression in two normal controls. A control protein actin is indicated below.

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