Hemophagocytic Lymphohistiocytosis, Familial, 3
A number sign (#) is used with this entry because hemophagocytic lymphohistiocytosis-3 (FHL3) is caused by homozygous or compound heterozygous mutation in the UNC13D gene (608897) on chromosome 17q25.
DescriptionSecretion of the contents of cytolytic granules at the immunologic synapse is a highly regulated process essential for lymphocyte cytotoxicity. This process requires the rapid transfer of perforin (170280)-containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane. Familial hemophagocytic lymphohistiocytosis is a genetically heterogeneous condition characterized by defective cytotoxicity. For a more detailed description of FHL, see 267700.
Clinical FeaturesFeldmann et al. (2003) identified a novel FHL subtype, FHL3, in 10 patients from 7 unrelated families. These patients presented with typical features of FHL, defined by early onset of overwhelming activation of T lymphocytes and macrophages and detection of activated CD8 (see 186910)-positive T lymphocytes in peripheral blood, in association with fever, hepatosplenomegaly, pancytopenia, coagulation abnormality, liver dysfunction, and features of hemophagocytosis in the bone marrow or cerebrospinal fluid. All 10 patients had defective anti-CD3 (see 186790)-driven cytotoxic T-cell activity, and intracellular perforin could be detected normally.
Santoro et al. (2006) reported 15 patients with FHL3 due to UNC13D mutation (see, e.g., 608897.0001, 608897.0006, and 608897.0009). Median age at diagnosis was 4 months, but 6 patients developed the disease after 5 years of age and 1 as a young adult of 18 years. Involvement of the central nervous system was present in 9 of 15 patients. Activity of natural killer cells was markedly reduced or absent in 13 patients who were tested. Chemoimmunotherapy was effective in all patients.
Rudd et al. (2008) reported 9 patients from 6 families with genetically confirmed FHL3. There was considerable variation in age at diagnosis, ranging from birth to 14 years, and 3 of the 9 mutation-positive patients developed central nervous system symptoms. Natural killer cell activity was impaired in all 4 patients studied. Defective cytotoxic lymphocyte degranulation was evident in the 2 patients investigated, and was more pronounced in the patient with onset during infancy than in the patient with adolescent onset.
InheritanceAn equal sex ratio among patients and a high frequency of consanguinity in the families with FHL3 reported by Feldmann et al. (2003) suggested autosomal recessive inheritance.
MappingBy genetic mapping and linkage analysis, Feldmann et al. (2003) mapped the FHL3 locus to a 17-cM region on chromosome 17q25.1.
Molecular GeneticsFeldmann et al. (2003) identified 6 different mutations in the UNC13D gene in 10 patients from 7 unrelated families with FHL3 (see 608897.0001-608897.0006).
In a Turkish patient from a consanguineous family with primary hemophagocytic lymphohistiocytosis, Zur Stadt et al. (2006) identified homozygosity for a missense mutation in the UNC13D gene (608897.0007).