Alternative titles; symbols
ORPHA: 540; DO: 0110923;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q25.1 | Hemophagocytic lymphohistiocytosis, familial, 3 | 608898 | Autosomal recessive | 3 | UNC13D | 608897 |
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.
Secretion 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.
Feldmann 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.
Bogaert et al. (2022) reported a girl with FHL3 who presented with cholestasis, splenomegaly, and marked thrombocytopenia 4 days after birth. Thrombocytopenia spontaneously normalized by day 15 of life, and cholestasis resolved by the end of the first month. At the age of 2 months, the patient had her first hemophagocytic lymphohistiocytosis (HLH) episode with high fever, marked hepatosplenomegaly, pancytopenia, hyperferritinemia, and hemophagocytosis in the bone marrow. The fever and neutropenia rapidly resolved without corticosteroid treatment. At age 4 months she had a second HLH episode with neutropenic fever and cardiorespiratory and neurologic symptoms. Despite treatment with dexamethasone, cyclosporine A, and antithymocyte globulin, she developed severe central nervous system findings, including refractory seizures and encephalopathy, and died at age 8 months. A molecular diagnosis of FHL3 was not made until she was 7 months of age. The authors emphasized that FHL3 can present with neonatal cholestasis and recommended that clinicians maintain a high index of suspicion of FHL3 when neonatal cholestasis is seen, especially when accompanied by persisting cytopenia and splenomegaly.
An 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.
Locatelli et al. (2020) investigated the efficacy and safety of emapalumab, a human anti-interferon-gamma (147570) antibody, administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving previously treated and untreated patients with primary hemophagocytic lymphohistiocytosis 18 years of age or younger. A total of 34 patients, 27 previously treated and 7 previously untreated, received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40%. In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. The authors concluded that emapalumab is an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis.
By genetic mapping and linkage analysis, Feldmann et al. (2003) mapped the FHL3 locus to a 17-cM region on chromosome 17q25.1.
Feldmann 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).
Bogaert, D., De Bruyne, R., Vanlander, A. V., Garabedian, L., Louis, Y., Haerynck, F., Bordon, V., De Moerloose, B. Familial hemophagocytic lymphohistiocytosis type 3 presenting as neonatal cholestasis and splenomegaly. (Letter) Pediat. Allergy Immun. 33: e13774, 2022. [PubMed: 35470934] [Full Text: https://doi.org/10.1111/pai.13774]
Feldmann, J., Callebaut, I., Raposo, G., Certain, S., Bacq, D., Dumont, C., Lambert, N., Ouachee-Chardin, M., Chedeville, G., Tamary, H., Minard-Colin, V., Vilmer, E., Blanche, S., Le Deist, F., Fischer, A., de Saint Basile, G. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115: 461-473, 2003. [PubMed: 14622600] [Full Text: https://doi.org/10.1016/s0092-8674(03)00855-9]
Locatelli, F., Jordan, M. B., Allen, C., Cesaro, S., Rizzari, C., Rao, A., Degar, B., Garrington, T. P., Sevilla, J., Putti, M. C., Fagioli, F., Ahlmann, M., Dapena Diaz, J.-L., Henry, M., De Benedetti, F., Grom, A., Lapeyre, G., Jacqmin, P., Ballabio, M., de Min, C. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. New Eng. J. Med. 382: 1811-1822, 2020. [PubMed: 32374962] [Full Text: https://doi.org/10.1056/NEJMoa1911326]
Rudd, E., Bryceson, Y. T., Zheng, C., Edner, J., Wood, S. M., Ramme, K., Gavhed, S., Gurgey, A., Hellebostad, M., Bechensteen, A. G., Ljunggren, H.-G., Fadeel, B., Nordenskjold, M., Henter, J.-I. Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis. J. Med. Genet. 45: 134-141, 2008. [PubMed: 17993578] [Full Text: https://doi.org/10.1136/jmg.2007.054288]
Santoro, A., Cannella, S., Bossi, G., Gallo, F., Trizzino, A., Pende, D., Dieli, F., Bruno, G., Stinchcombe, J. C., Micalizzi, C., De Fusco, C., Danesino, C., Moretta, L., Notarangelo, L. D., Griffiths, G. M., Arico, M. Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis. (Letter) J. Med. Genet. 43: 953-960, 2006. [PubMed: 16825436] [Full Text: https://doi.org/10.1136/jmg.2006.041863]
Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum. Mutat. 27: 62-68, 2006. [PubMed: 16278825] [Full Text: https://doi.org/10.1002/humu.20274]