Introduction

Although the earliest report of the inherited condition, now known as familial hemophagocytic lymphohistiocytosis (FHL) (OMIM 603552, 603553, 602782, 170280), is traditionally attributed to Farquhar and Claireaux (1952), it was not until 1995 that a logical framework for the understanding of these conditions was provided (Henter and Elinder, 1995; Henter, 2002). According to this schema, hemophagocytic lymphohistiocytosis (HLH) with an underlying genetic defect is regarded as ‘primary HLH’. All other forms are reactive, examples of the macrophage activation syndrome, and hence, ‘secondary HLH’. The ‘contemporary classification of histiocytic disorders’ (Favara et al., 1997) lists primary HLH as including a clearly familial form as well as a sporadic form without a clear family history, nonetheless thought to be genetic, and secondary hemophagocytic syndromes that are infection or malignancy associated. Curiously, it is not the histiocyte (monocyte-macrophage) that is abnormal in either form. In primary HLH there is a defect in the control of the inflammatory process, such as perforin mutations, that leads to the activation and accumulation of macrophages. In secondary HLH, the macrophage activation appears to be driven by cytokines following a trigger. It is however, becoming apparent that even in secondary, reactive macrophage activation type HLH, there may be an inherited predisposition in the form of reactive versus non-reactive polymorphisms for certain receptors and response molecules such as IL-10, IL-12 and IL-18 (Lammas et al., 2002; Fujihara et al., 2003; Goldstein et al., 2003).