These cases of HLH are classified as belonging to the class of Epstein–Barr_virus–associated_lymphoproliferative_diseases and termed EBV+ HLH. 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)/UNC18-2Nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations. Pathophysiology
The underlying causes, either inherited or acquired, lead to an unchecked immune response when exposed to triggers. Impaired NK-cell cytotoxicity is the hallmark of HLH. All genetic defects for familial HLH are related to granule-dependent cytotoxicity. This inability to remove infected and antigen-presenting cells and terminate the immune response leads to uncontrolled proliferation and activation of the immune system with release of excessive cytokines. These cells then infiltrate organs, releasing more cytokines, which gives the clinical picture. The fever is caused by IL-1, IL-6 and TNF-alpha; the cytopenia is due to the suppressive effect on hematopoiesis by TNF-alpha and TNF-gamma. TNF-alpha and TNF-gamma may also lead to inhibition of lipoprotein lipase or stimulate triglyceride synthesis.
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 g/100 ml (in infants <4 weeks: haemoglobin <10 g/100 ml) (anemia)
Platelets <100×109/L (thrombocytopenia)
Neutrophils <1×109/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 HLH, no evidence of malignancy should be apparent. Not all five out of eight criteria are required for diagnosis of HLH 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 HLH patients. Attempts to improve diagnosis of HLH have included use of the HScore, which can be used to estimate an individuals risk of HLH. In adults, soluble IL-2 receptor has been found to be a very sensitive marker for HLH, demonstrating 100% sensitivity for ruling out HLH 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.