Hemophagocytic Lymphohistiocytosis and Primary Immunodeficiency Disorders – follow up

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled inflammation that is often lethal if not diagnosed and treated promptly. HLH has often been designated as “primary” (genetic) if mutations in genes important for cytotoxic T and NK cell function or in genes causing primary immunodeficiency disorders (PID) have been identified. Triggers such as infections, malignancy and rheumatic diseases have been implicated as causes for the “secondary” (acquired) form of HLH. The terminology of primary versus secondary HLH, although useful in the past, can be misleading as primary HLH might be triggered by secondary causes such as infections, and conversely, genetic mutations are identified at increasing frequency among patients with HLH that was considered secondary. Here we update the growing list of PID associated with HLH. In addition to the more common defects in granule-mediated cytotoxicity caused by mutations in perforin, UNC13D, STX11, STXBP2), LYST, RAB27A, SH2D1A and XIAP, we describe mutations which disrupt T cell development and function. These include 22q11 deletion syndrome, Wiskott Aldrich syndrome, STAT1 deficiency and others. Interestingly, HLH can also occur among patients with auto-inflammatory disease and immune dysregulation.  Importantly, the occurrence of HLH among patients with defects restricted to T cells, suggests that a combination of increased susceptibility to infections with loss of T cell function might be sufficient for development of uncontrolled inflammatory response and HLH.