8.4Familial Erythrophagocytic Lymphohistiocytosis (FEL)

8.4.1Definition

•Familial occurrence with autosomal recessive inheritance

–Association with X linked lymphoproliferative syndrome, Chediak–Higashi*, Griscelli type-2 * (*with oculocutaneous albinism)

–Unknown mutation, occurrence in Turkish population

•First occurrence usually in infancy

•Also described as isolated occurrence without familial history

8.4.2Pathology and Genetics

•Histopathologically characterized by diffuse, mixed lymphohistiocytic infiltra- tion with erythrophagocytosis or hemophagocytosis

•Disturbance of cellular and humoral immunity, particularly of cytotoxic T-lymphocytes and natural killer cells and high production of proinflammatory cytokines

•Occasional monoclonal gammopathy

•Chromosomal abnormalities of chromosomes 9q21.3–22 and 10q21–22 (10q21–22 is the gene locus of associated perforin deficiency)

•The UNC13 genes, which are involved in cytolytic granule movement, are also mutated in some forms of inherited HLH

8.4.3Clinical Presentation

•Manifestation within the first 3 months of life in the majority of patients; in a minority, first occurrence within the first 4 years of life

•Nonspecific symptomatology such as fever, pallor, vomiting, diarrhea, anorexia, irritability

•Often lymphadenopathy and hepatosplenomegaly

•Often multiorgan involvement. Lung, liver, and CNS: diffuse perivascular and parenchymal infiltrates with or without involvement of cerebral spinal fluid. Eyes: infiltration of vitreous cavity, uvea, iris, retina, choroid, and optic nerve; pleural and peritoneal effusions may be seen

•Coagulopathy with hemorrhagic diathesis (high D-dimers, low fibrinogen, increased PT and PTT) may be present

8.4.4Laboratory Analyses

•Pancytopenia is common

•Bone marrow with erythrophagocytosis and high numbers of histiocytes, lymphocytes, precursor cells of all cell lines with maturation arrest and hyperplasia of erythropoiesis, hemophagocytosis may be present