Light microscopic image of bone marrow showing stromal macrophages containing numerous red blood cells in their cytoplasmThe blood count typically shows decreased numbers of blood cells—including a decreased number of circulating red blood cells, white blood cells, and platelets. The bone marrow may show hemophagocytosis. The liver function tests are usually elevated. A low level of the protein albumin in the blood is common. The serum C reactive protein, erythrocyte sedimentation rate, and ferritin level are markedly elevated. In children, a ferritin above 10000 is very sensitive and specific for the diagnosis of<unk> , however, the diagnostic utility for ferritin is less for adult<unk>  patients. The serum fibrinogen level is usually low and the D-dimer level is elevated. The sphingomyelinase is elevated. Bone marrow biopsy shows histiocytosis. Classification Primary<unk> , also known as familial<unk>  (FHL) or familial erythrophagocytic<unk> , is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity. Secondary<unk>  (acquired<unk>  occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and haematologic alterations and death in the absence of treatment. A subtype of primary<unk>  where the inflammation is limited to the central nervous system has been described. Diagnostic criteria The current (2008) diagnostic criteria for<unk>  are 1. A molecular diagnosis consistent with<unk> . These include the identification of pathologic mutations of PRF1, UNC13D, or STX11. OR 2. Fulfillment of five out of the eight criteria below: * Fever (defined as a temperature >100.3 °F, >38 °C) * Enlargement of the spleen * Decreased blood cell counts affecting at least two of three lineages in the peripheral blood: * Haemoglobin 9/L (thrombocytopenia) * Neutrophils 9/L (neutropenia) * High blood levels of triglycerides (fasting, greater than or equal to 265 mg/100 ml) and/or decreased amounts of fibrinogen in the blood (≤ 150 mg/100 ml) * Ferritin ≥ 500 ng/ml * Haemophagocytosis in the bone marrow, spleen or lymph nodes * Low or absent natural killer cell activity * Soluble CD25 (soluble IL-2 receptor) >2400 U/ml (or per local reference laboratory) In addition, in the case of familial<unk> , no evidence of malignancy should be apparent. Not all five out of eight criteria are required for diagnosis of<unk>  in adults, and a high index of suspicion is required for diagnosis as delay results in increased mortality. The diagnostic criteria were developed in pediatric populations and have not been validated for adult<unk>  patients. Attempts to improve diagnosis of<unk>  have included use of the HScore, which can be used to estimate an individual's risk of<unk> . In adults, soluble IL-2 receptor has been found to be a very sensitive marker for<unk> , demonstrating 100% sensitivity for ruling out<unk>  below a cutoff of 2400 U/mL and optimal cutoff for ruling in at 2515 U/mL (sensitivity, 100%; specificity, 72.5%), with 93% specificity at >10 000 U/mL. Differential diagnosis The differential diagnosis of<unk>  includes secondary<unk>  and macrophage-activation syndrome or other primary immunodeficiencies that present with<unk> , such as X-linked lymphoproliferative disease. Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome. As a syndrome of intense inflammation it needs to be differentiated from sepsis, what may be extremely challenging. The diagnosis of acquired, or secondary,<unk>  is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired<unk>  may have decreased, normal, or increased NK cell activity. Griscelli syndrome A major differential diagnosis of<unk>  is Griscelli syndrome (type 2). This is a rare autosomal recessive disorder characterized by partial albinism, hepatosplenomegaly, pancytopenia, hepatitis, immunologic abnormalities, and<unk> . Most cases have been diagnosed between 4 months and 7 years of age, with a mean age of about 17 months. Three types of Griscelli syndrome are recognised: type 1 has neurologic symptoms and mutations in MYO5A. Prognosis depends on the severity of neurologic manifestations. Type 2 has mutations in RAB27A and<unk>  syndrome, with abnormal T-cell and macrophage activation. This type has a grave prognosis if untreated. Type 3 has mutations in melanophilin and is characterized by partial albinism. This type does not pose a threat to those so affected.
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