Hemophagocytic lymphohistiocytosis and primary immune deficiency disorders

Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency

“…The underlying genetic mechanisms have been elucidated in the last few years in less than 10% to 15% of the cases and involve mutations in CD19, MS4A1 (CD20), CR2 (CD21), ICOS, TNFRSF13C, TNFRSF13B, PLCG2 (phospholipase Cg2), CD81, LRBA, and PRKCD (protein kinase Cd). [1][2][3] Recently, germline heterozygous mutations in NFKB2 were identified in 10 patients to be associated with early-onset CVID with autoimmunity in most cases, 4,5 profound B-cell deficiency, 6 or a CVID-like phenotype. 7 All affected patients had hypogammaglobulinemia with variable association of the following clinical and immunologic features: central adrenal insufficiency (ACTH insufficiency), alopecia totalis or areata, trachyonychia, variable natural killer (NK) cell numbers, and defects in peripheral T and B cells.…”

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis

“…Single cases or small case series of HLH syndrome have been reported in a variety of PID, and the clinical presentation of some of these cases has recently been summarized. 11 However, a multicenter systematic analysis of the clinical and laboratory features of HLH syndrome in these patients in comparison to HLH associated with defects in lymphocyte cytotoxicity has not been performed. We reasoned that such an analysis might offer the opportunity to identify parameters for differential diagnosis, facilitating early identification of patients with hemophagocytic inflammatory disease in whom aggressive immunosuppressive therapy may be contraindicated.…”

Hemophagocytic lymphohistiocytosis in a patient with CD3δ deficiency

“…Although the precise mechanism leading to HLH in CD3δ deficiency remains to be determined, it is plausible to assume that the absence of cytotoxic T cells, even in the presence of normal NK cells, may be a critical predisposing factor (George 2014). This has also been observed in some case reports of PID that are not typically affecting the NK cell number or function (Introne et al 1999;Menasche et al 2000;Cesaro et al 2003;Pasic et al 2003;Faitelson and Grunebaum 2014). It might be related, at least partially, to the lack of defense mechanisms against infectious triggers known to predispose to HLH (Faitelson and Grunebaum 2014).…”

“…Indeed, HLH has been reported in a growing number of T-cell PID in which normal immune surveillance is lost, such as X-linked SCID (Grunebaum and Roifman 2002), Zap70 deficiency, and others. A recent published paper has reviewed the association between HLH and PID (Faitelson and Grunebaum 2014).…”

“…In contrast, a growing number of PID with no obvious NK-cell defect have also been found to predispose patients to HLH, suggesting that failure of NK activity is not the only mechanism leading to this unusual form of inflammation. Wiskott-Aldrich syndrome, DiGeorge syndrome (primarily the 22q11.2 microdeletion syndrome), and STAT1 deficiency are prime examples (Introne et al 1999;Menasche et al 2000;Cesaro et al 2003;Pasic et al 2003;Faitelson and Grunebaum 2014). It is possible that the lack of cytotoxic T-cell function might play a role in this predisposition.…”