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

HLH: genomics illuminates pathophysiological diversity

“…A definitive molecular diagnosis of fHLH was only achieved in a limited number of patients (n 5 19; 19%), with fHLH overrepresented in infants diagnosed before 1 year of age (61%). By exome sequencing, a group of patients were diagnosed with other well-known PIDs, such as Omenn syndrome, chronic granulomatous disease, and autoimmune lymphoproliferative syndrome, corroborating previous findings from Bode et al 4 Taking advantage of a large cohort of individuals undergoing sequencing with the exome platform at the Baylor-Hopkins Center for Mendelian Genomics, the authors were also able to test for enrichment of digenic inheritance in patients fulfilling HLH-2004 criteria compared with nearly 6000 control individuals. In their data, they did not find statistical support for a digenic model of susceptibility to HLH.…”

“…3 For example, metabolic disorders and other primary immunodeficiency diseases (PIDs) occasionally present with HLH, thus falling under the umbrella of secondary HLH. 4,5 However, the degree to which genetic factors predispose patients to secondary HLH has not been comprehensively determined.…”

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages

“…These HLH-like syndromes are not to be considered as true primary HLH, they are frequently triggered by Epstein-Barr virus infection causing B lymphoproliferation. 91 Secondary HLH may occur at any age, and the first clinical symptoms are usually associated with an infectious episode, rheumatic condition, or malignancy. 92 The clinical course may be severe, and the mortality is still significant.…”

Gene-corrected human Munc13-4–deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice

“…4 The condition often appears to be triggered by a viral infection (Epstein-Barr virus [EBV], in particular). [5][6][7] Hematopoietic stem cell transplantation (HSCT) is the only available curative option for FHL3; however, the posttreatment overall survival rate is not satisfactory and depends on (1) the disease state prior to HSCT and (2) the availability of a matched sibling donor. 4 In addition to HSCT, gene therapy of hematopoietic stem cells has been tested as a treatment of FHL2 in a murine model.…”