Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of uncontrolled immune activation leading to extreme inflammation. Primary HLH was once believed to be a disease that occurred only in infancy or young children, and was rarely diagnosed in adults. It is now understood that patients can develop primary HLH in their adolescence or adulthood. This study included 252 adolescent and adult patients with a clinical diagnosis of HLH from 35 general medical institutions across mainland China. All exons and 50 bp of flanking intronic sequence of six HLH-related genes (PRF1, UNC13D, STX11, STXBP2, SH2D1A, and BIRC4) were sequenced in these patients. We identified mutations in 18/252 (7.1%) of the patients, with changes in PRF1 being most common. Late-onset HLH often features viral infection and other predisposing factors. We conclude that late-onset primary HLH is not as rare as previously thought. Older patients should not be delayed to receive HLH-related genes testing when they are suspected with HLH.
Highlights
Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder characterized by the uncontrolled activation of T lymphocytes and macrophages and the excessive generation of inflammatory cytokines
All coding exons and at least 50 base pairs of the adjacent intronic sequence of the six genes associated with HLH (PRF1, UNC13D, STX11, STXBP2, SH2D1A, and BIRC4) were PCR amplified and sequenced
The patient sequences were compared to those published in Genbank (PRF1, NM_005041.4; STX11, NM_003764.3; SH2D1A, NM_002351.3; UNC13D, NM_199242.2; BIRC4, NM_001167.2; STXBP2, NM_006949.2)
Summary
Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder characterized by the uncontrolled activation of T lymphocytes and macrophages and the excessive generation of inflammatory cytokines. The disease presents clinically with persistent fever, hepatosplenomegaly, pancytopenia, and hemophagocytic phenomena detected in the bone marrow, liver, spleen, and lymph tissue, with onset typically occurring in the first 2 years of life. Primary HLH ( called familial HLH) refers to cases in which there is a positive family history or a defined genetic cause. An onset of primary HLH after 8 years of age has rarely been reported [1]. A hallmark of the disease is decreased NK cell and cytotoxic T lymphocyte (CTL) function, which is thought to be caused by genetic defects in the perforin/granzyme-mediated cytotoxic pathway. Uncontrolled immune activation leading to extreme inflammation causes the onset of HLH symptoms [2]. The HLH-94 treatment protocol involves the use of corticosteroids, cyclosporine A, and etoposide before hematopoetic stem cell transplant (HCT) [3]
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