Genetic alterations in primary HLH and related disorders of immunoregulation
| Defective immune function . | Gene* (locus) . | Syndrome . | Clinical features . | Laboratory findings . |
|---|---|---|---|---|
| Cytotoxic granule content | PRF1 (10q21-22) | FHL2 | Decreased/absent perforin expression (FC) | |
| Cytotoxic exocytosis pathway | UNC13D (17q2) | FHL3 | Low CD107a expression (degranulation assay, FC) | |
| STX11 (6q24) | FHL4 | Low CD107a expression (degranulation assay, FC) | ||
| STXBP2 (19p13) | FHL5 | Colitis, sensorineural hearing loss | Low CD107a expression (degranulation assay, FC) | |
| RAB27A (15q21) | Griscelli type 2 | Hypopigmentation | Abnormal granule pattern in CBC and hair shafts, low CD107a expression | |
| LYST (1q42-43) | Chediak-Higashi | Hypopigmentation | Abnormal granule pattern in CBC and hair shafts, low CD107a expression | |
| Cytotoxic T-cell signaling | SH2D1A (Xq24-25) | XLP1 Duncan disease | EBV lymphoproliferation | Decreased/absent SAP expression, reduced NK T cells (FC), hypogammaglobulinemia |
| Inflammasome regulation, excess apoptosis, NOD signal | BIRC4 (Xq25) | Refractory colitis, EBV lymphoproliferation | Decreased/absent BIRC4 protein expression, reduced NK T cells | |
| Inflammasome constitutive activation | NLRC4 (2p22.3) | XLP2 | Recurrent autoinflammation, enterocolitis | High circulating IL-18 levels |
| Defective immune function . | Gene* (locus) . | Syndrome . | Clinical features . | Laboratory findings . |
|---|---|---|---|---|
| Cytotoxic granule content | PRF1 (10q21-22) | FHL2 | Decreased/absent perforin expression (FC) | |
| Cytotoxic exocytosis pathway | UNC13D (17q2) | FHL3 | Low CD107a expression (degranulation assay, FC) | |
| STX11 (6q24) | FHL4 | Low CD107a expression (degranulation assay, FC) | ||
| STXBP2 (19p13) | FHL5 | Colitis, sensorineural hearing loss | Low CD107a expression (degranulation assay, FC) | |
| RAB27A (15q21) | Griscelli type 2 | Hypopigmentation | Abnormal granule pattern in CBC and hair shafts, low CD107a expression | |
| LYST (1q42-43) | Chediak-Higashi | Hypopigmentation | Abnormal granule pattern in CBC and hair shafts, low CD107a expression | |
| Cytotoxic T-cell signaling | SH2D1A (Xq24-25) | XLP1 Duncan disease | EBV lymphoproliferation | Decreased/absent SAP expression, reduced NK T cells (FC), hypogammaglobulinemia |
| Inflammasome regulation, excess apoptosis, NOD signal | BIRC4 (Xq25) | Refractory colitis, EBV lymphoproliferation | Decreased/absent BIRC4 protein expression, reduced NK T cells | |
| Inflammasome constitutive activation | NLRC4 (2p22.3) | XLP2 | Recurrent autoinflammation, enterocolitis | High circulating IL-18 levels |
CBC, complete blood count; EBV, Epstein-Barr virus; FC, flow cytometry; NOD, nucleotide-binding oligomerization domain-like receptor; SAP, SLAM-associated protein; XLP, X-linked lymphoproliferative syndrome.
Genes associated with other rare immune deficiencies that may cause the HLH syndrome include ITK (5q33), CD27 (12p13.31), RAG1&2 (11p12), IL2RG (Xq13.1), IL7RA (5p13.2), CD3E (11q23.3), BTK (Xq22.1), FAS (10q23.31), WAS (Xp11.23), ATM (11q22.3), NEMO (Xq28), STAT1 (2q32.2), DKC1 (Xq28), MEFV (16p13.3), and TNFRSF1A (12p13.31), as well as CYBB (Xp21.1-p11.4), CYBA (16q24.2), and NCF1 (7q11.23) which encode the phagocyte reduced NAD phosphate oxidase complex affected in chronic granulomatous disease.13,46,124