There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH). There are five subtypes of inherited (or familial) HLH which are designated familial HLH, types 1-5. Each subtype is caused by a change (mutation) in a different gene that helps regulate the immune system. Type 1 is due to a gene defect on chromosome 9. Familial HLH, type 2 is caused by mutations in the PRF1 gene. Familial HLH, type 3 is caused by mutations in the UNC13D gene. Familial HLH, type 4 is caused by mutations in the STX11 gene. Familial HLH, type 5 is caused by mutations in the STXBP2 gene.

All of the genes involved with HLH normally provide instructions for proteins that help destroy or turn off activated immune cells when they are no longer needed. Changes in these genes lead to an overproduction of immune cells which results in an excessive immune response and the many signs and symptoms of familial HLH.

The acquired causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases. When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.

Inheritance
Hemophagocytic lymphohistiocytosis (HLH) may be inherited or acquired (due to non-genetic factors).

Familial HLH is inherited in an autosomal recessive manner. This means that to be affected, a person must have a change (mutation) in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Acquired HLH is not inherited. The non-genetic causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases.

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.