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Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder due to dysregulation of the immune system.The predominant symptoms are persistent fever, cytopenias,hepatosplenomegaly, hepatitis, sometimes associated with hyper-ferritinemia, hemophagocytosis, and NK cell dysfunction [1–4].Familial HLH (FHL) is genetically heterogeneous and inherited inan autosomal recessive manner. To date, four genes have beenidentified as causative, namely, PRF1 (FHL2, OMIM 603553),UNC13D(FHL3,OMIM608898),STX11(FHL4,OMIM603552),and STXBP2 (FHL5, OMIM 613101) [5–8]. Mutations in PRF1,UNC13D, and STXBP2 account for approximately 60% of FHLcases in North American patients [9]. Furthermore, mutations inseveral other genes such as SH2D1A (OMIM 300490), BIRC4(OMIM 300079), LYST (OMIM 606897), RAB27A (OMIM603868), and AP3B1 (OMIM 603401) have been associated withepisodes of HLH [10–14].Functionally, all of these genes encode for proteins required forthe granzyme/perforin-mediated cytotoxic pathway that regulatesNK cell and cytotoxic lymphocyte-triggered apoptosis. Theperforin (encoded by PRF1) is a pore-forming cytolytic proteinsynthesized in cytotoxic lymphocytes, along with cytotoxic cellproteinase Granzyme B, are enveloped in secretory vesicles. Ingeneral, the mutations in PRF1 (FHL2) results in absent or markeddecrease of perforin expression [5,9]. UNC13D, STX11, andSTXBP2 encode proteins that are responsible for fusion andtrafficking of the granule exocytosis towards the target cells.Mutations in these genes (FHL3, 4, and 5) usually are associatedwithdefectiveexpressionofCD107ainNKcells,whilethelevelofperforin could be normal or increased [6–9]. In most of FHL andsecondaryHLH,thelevelofGranzymeBistypicallyincreased[9].In particular, UNC13D plays an essential role together withRAB27A to form a complex that primes the fusion of the lyticgranules with the plasma membrane, and mutations in either of thetwo genes prevent the formation of the complex that consequentlyabolishessecretion[15,16].Approximatelyone-hundredmutationsin UNC13D have been described to date [6,7,17,18]. Meethset al. [19] first reported a 253-kb inversion straddling the last twoexons of the gene and downstream intergene region and adeep intronic mutation c.118–308C>T mutation in Europeanpatients affected with FHL3 [19]. Another deep intronic mutation |
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