IllnessLymphohistiozytosis, familial hemophagocytic; differential diagnosis

NGS +

In familial hemophagocytic lymphohistiocytosis the immune system produces too many activated cells (B, T, natural killer cells, macrophages/histiocytes) as well as excessive cytokine levels. The over-activation of the immune system leads to fever as well as liver and spleen damage. As the disease progresses, hematopoietic cells in the bone marrow are destroyed by hemophagocytosis, resulting in anemia as well as thrombocytopenia and bleeding. Neurological symptoms such as paralysis, blindness, seizures and coma are observed with additional cardiac and renal involvement. The risk of developing leukemia and lymphoma is increased. First symptoms usually appear in infancy, occasionally later. Half of the familial cases develop on the basis of mutated PRF1 or UNC13D genes, but mutations in more than two dozen other genes do not even explain all other cases. In the guidelines more than two dozen gene candidates are mentioned. The inheritance pattern is often autosomal recessive.

References: https://www.frontiersin.org/articles/10.3389/fimmu.2014.00167/full

https://www.ncbi.nlm.nih.gov/books/NBK1406/

• Allelic: Aplastic anemia (PRF1)
• Allelic: Breast cancer, susceptibility to (ATM)
• Allelic: Familial cold autoinflammatory syndrome 4 (NLRC4)
• Allelic: Lymphoma, non-Hodgkin (PRF1)
• Allelic: Multiple sclerosis, susceptibility to, 5 (TNFRSF1A)
• Agammaglobulinemia, XL 1 (BTK)
• Ataxia-telangiectasia (ATM)
• Autoimmune lymphoproliferative syndrome (FAS)
• Autoimmune lymphoproliferative syndrome, type IA (FAS)
• Autoinflammation with infantile enterocolitis (NLRC4)
• Chediak-Higashi syndrome (LYST)
• Chronic granulomatous disease 1, AR (NCF1)
• Chronic granulomatous disease 4, AR (CYBA)
• Chronic granulomatous disease, XLR (CYBB)
• Combined cellular + humoral immune defects with granulomas (RAG1, RAG2)
• Combined immunodeficiency, XL, moderate (IL2RG)
• Dyskeratosis congenita, XL (DKC1)
• Ectodermal dysplasia + immunodeficiency 1 (IKBKG)
• Familial Mediterranean fever, AD + AR (MEFV)
• Griscelli syndrome, type 2 (RAB27A)
• Hemophagocytic lymphohistiocytosis, familial, 2 (PRF1)
• Hemophagocytic lymphohistiocytosis, familial, 3 (UNC13D)
• Hemophagocytic lymphohistiocytosis, familial, 4 (STX11)
• Hemophagocytic lymphohistiocytosis, familial, 5 (STXBP2)
• Immune dysregulation + systemic hyperinflammation syndrome (RC3H1)
• Immunodeficiency 18 (CD3E)
• Immunodeficiency 18, SCID variant (CD3E)
• Immunodeficiency 31A, mycobacteriosis, AD (STAT1)
• Immunodeficiency 31B, mycobacterial + viral infections, AR (STAT1)
• Immunodeficiency 31C, chronic mucocutaneous candidiasis, AD (STAT1)
• Immunodeficiency 33 (IKBKG)
• Immunodeficiency 34, mycobacteriosis, XL (CYBB)
• Incontinentia pigmenti (IKBKG)
• Isolated growth hormone deficiency, type III, with agammaglobulinemia (BTK)
• Lymphoproliferative syndrome 1 (ITK)
• Lymphoproliferative syndrome 2 (CD27)
• Lymphoproliferative syndrome, XL, 1 (SH2D1A)
• Lymphoproliferative syndrome, XLL, 2 (XIAP)
• Neutropenia, severe congenital, XL (WAS)
• Neutrophilic dermatosis, acute febrile (MEFV)
• Omenn syndrome (RAG1, RAG2)
• Periodic fever, familial (TNTRSF1A)
• Severe combined immunodeficiency, B cell-negative (RAG1, RAG2)
• Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type (IL7R)
• Severe combined immunodeficiency, XL (IL2RG)
• T-cell lymphoma, subcutaneous panniculitis-like (HAVCR2)
• Takenouchi-Kosaki [macrothrombocytopenia + mental retardation] syndrome (CDC42)
• Thrombocytopenia, XL (WAS)
• Thrombocytopenia, XL, intermittent (WAS)
• Wiskott-Aldrich syndrome (WAS)
• a/b T-cell lymphopenia with g/d T-cell expansion, severe cytomegalovirus infect., autoimmun. (RAG1)