Hemophagocytic lymphohistiocytosis, familial 3 D81.4

Haemophagocytic lymphohistiocytosis, familial type 3, or FHL3, is a rare immunodeficiency syndrome caused by a homozygous or compound heterozygous mutation in the UNC13D gene (608897) on chromosome 17q25.

The secretion of the contents of cytolytic granules at the immunological 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. For a more detailed description of FHL, see Haemophagocytic lymphohistiocytosis, familial (review).

Feldmann et al (2003) identified 6 different mutations in the UNC13D gene in 10 patients from 7 unrelated families with FHL3 (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).

In the collective of Santoro et al. (2006), the mean age at diagnosis was 4 months. 6 patients developed the disease at the age of 5 years and 1 patient at the age of 18 years.

Feldmann et al (2003) identified a new FHL subtype, FHL3, in 10 patients from 7 unrelated families. These patients had the typical features of familial hemophagocytic lymphohistiocytosis, characterized by early-onset, overwhelming activation of T lymphocytes and macrophages and evidence of activated CD8 (reviewed in 186910)-positive T lymphocytes in peripheral blood in association with fever, hepatosplenomegaly, pancytopenia, coagulopathy, liver dysfunction, and features of hemophagocytosis in bone marrow or cerebrospinal fluid. All 10 patients had defective anti-CD3-driven cytotoxic T-cell activity. Intracellular perforin was detected normally.

Santoro et al (2006) reported 15 patients with FHL3 due to a UNC13D mutation. The central nervous system was affected in 9 of 15 patients. Natural killer cell activity was markedly reduced or absent in 13 patients studied. Chemoimmunotherapy was effective in all patients.

Rudd et al (2008) reported 9 patients from 6 families with genetically confirmed FHL3. 3 of the 9 patients developed central nervous system symptoms. Natural killer cell activity was impaired in all 4 patients studied. Defective cytotoxic lymphocyte degranulation was seen in 2 patients studied, and it was more pronounced in the patient with onset in infancy than in the patient with onset in adolescence.

1. Feldmann J et al (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115: 461-473.
2. Locatelli F et al (2020) Emapalumab in children with primary hemophagocytic lymphohistiocytosis. New Eng J Med 382: 1811-1822.
3. Rudd E et al (2008) Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis. J Med Genet 45: 134-141.
4. Santoro A et al (2006) Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. (Letter) J Med Genet 43: 953-960.
5. Zur Stadt U et al. (2006) Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum Mutat 27: 62-68.