Primary<unk>  is caused by loss of function, (i.e. inactivating) mutations in genes that code for proteins cytotoxic T cells and NK cells use to kill targeted cells, such as those infected with pathogens like the Epstein-Barr virus (EBV) or the Dengue virus. These mutations include those in the following genes: UNC13D, STX11, RAB27A, STXBP2, LYST, PRF1 1, SH2D1A, BIRC4, ITK, CD27, and MAGT1. Secondary<unk>  (sHLH) is associated with, and thought to be promoted, by malignant and non-malignant diseases that likewise weaken the ability of the immune system to attack EBV-infected cells. Malignant disorders associated with secondary<unk>  include T-cell lymphoma, B-cell lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, and myelodysplastic syndrome. Non-malignant disorders associated with secondary<unk>  include: autoimmune disorders such as juvenile idiopathic arthritis, juvenile Kawasaki disease, systemic lupus erythematosus, the juvenile onset and adult onset forms of Still's disease, and rheumatoid arthritis; immunodeficiency disorders such as severe combined immunodeficiency, DiGeorge syndrome, Wiskott–Aldrich syndrome, ataxia–telangiectasia, and dyskeratosis congenita); and infections caused by EBV, cytomegalovirus, HIV/AIDS, bacteria, protozoa, fungi and SARS-CoV-2. Secondary<unk>  may also result from iatrogenic causes such as bone marrow or other organ transplantations; chemotherapy; or therapy with immunosuppressing agents; About 33% of all<unk>  cases, ~75% of Asian<unk>  cases, and nearly 100% of<unk>  cases caused by mutations in SH2D1A (see X-linked lymphoproliferative disease type 1) are associated with, and thought triggered or promoted by, EBV infection. These cases of<unk>  are classified as belonging to the class of Epstein–Barr virus-associated lymphoproliferative diseases and termed EBV+<unk> . Genetics Five genetic subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described, with an estimated overall prevalence of one in 50,000 and equal gender distribution. Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis. Symptoms of FHL are usually evident within the first few months of life and may even develop in utero. However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases. The five subtypes of FHL are each associated with a specific gene: * FHL1: HPLH1 * FHL2: PRF1 (Perforin) * FHL3: UNC13D (Munc13-4) * FHL4: STX11 (Syntaxin 11) * FHL5: STXBP2 (Syntaxin binding protein 2)/UNC18-2 Nearly half of the cases of type 2 familial<unk>  are due to bi-allelic PRF1 mutations.
Hemophagocytic lymphohistiocytosis
Diffuse infiltrative lymphocytosis syndrome
Congenital self-healing reticulohistiocytosis
Thymoma with immunodeficiency
Langerhans cell histiocytosis
Blastic plasmacytoid dendritic cell neoplasm
Hereditary pyropoikilocytosis
Angioimmunoblastic T-cell lymphoma