Summary

Familial Hemophagocytic lymphohistiocytosis (FHL) is characterized by a macrophage activation syndrome usually occurring after a healthy period that may range from several months after the birth to, more rarely, several years. The syndrome affects about 1 in 50,000 births and is usually triggered by viral infection. In most cases, the first signs include unexplained high fever, irritability, general pain, oedema and hepatosplenomegaly. The syndrome is transmitted in an autosomal recessive manner. Recent studies have shown that FHL is genetically heterogeneous, it may be caused by at least three different genes: one is located in 10q21-22, a second in 9q21-22, while the other gene or genes has/have not yet been located. Presently, no phenotypic criteria can distinguish between FHL caused by the different genetic anomalies. The gene located on 10q21-22 has been identified as coding for perforin, but gene anomalies differ from one family to another. Perforin is a protein that is specifically expressed in T and NK cytotoxic cells and is required for their cytotoxic activity. Its action in FHL demonstrates its primary role in immune regulation. When their mutation has been identified, families belonging to this genetic group can be offered prenatal diagnosis. More recently, the causative gene responsible for approximately 33% of cases was identified. This MUNC13-4 gene encodes a protein involved in the mechanism of cytotoxic granule exocytosis. Prenatal diagnosis is also possible for families carrying this mutation. Biologically, pancytopenia associated with hepatic cytolysis, hypertriglyceridemia, fibrinopenia, hemodilution and neurological abnormalities may appear, as well as the infiltration of the various organs by activated lymphocytes and macrophages having phagocytosed red blood cells. Immunologically, NK cells show defective cytotoxic activity. Activation of lymphocytes is mainly of the CD8 type and is evidenced by cell surface markers such as HLA class II, by a high serum concentration of CD8s and CD25s, and by the significant secretion of gamma IFN. The activated macrophages secrete large amounts of IL1 and alpha TNF, which seems to be the cause of most clinical and biological signs. Macrophage activation syndrome is also found in Chediak-Higashi disease, Griscelli disease (both diseases are also marked by partial albinism) or X-linked lymphoproliferative disease (XLP). The same features can also be seen in what are called acquired forms of the syndrome, which can be triggered by an infection, autoimmune diseases, severe forms of hystiocytosis, or more rarely during chemotherapy in a patient with a malignant disorder. Differential diagnosis is based on the fact that FHL is associated with isolated macrophage activation, early onset and recurrent episodes. The only cure for FHL is bone marrow transplantation, preceded by a treatment associating corticotherapy and anti thymocyte Immunoglobulin (ATG) to control macrophage activation. Intrathecal injections of methotrexate prevent or cure neuromeningeal disorders.

Expert reviewer(s)

• Dr Geneviève DE SAINT-BASILE - CHAZELAS