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Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH
Open accessAbstract
Familial hemophagocytic lymphohistiocytosis (HLH) is a rare primary immunodeficiency disorder characterized by defects in cell-mediated cytotoxicity that results in fever, hepatosplenomegaly, and cytopenias. Familial HLH is well recognized in children but rarely diagnosed in adults. We conducted a retrospective review of genetic and immunologic test results in patients who developed HLH in adulthood. Included in our study were 1531 patients with a clinical diagnosis of HLH; 175 patients were 18 years or older. Missense and splice-site sequence variants in PRF1, MUNC13-4, and STXBP2 were found in 25 (14%) of the adult patients. The A91V-PRF1 genotype was found in 12 of these patients (48%). The preponderance of hypomorphic mutations in familial HLH–causing genes correlates with the later-onset clinical symptoms and the more indolent course in adult patients. We conclude that late-onset familial HLH occurs more commonly than was suspected previously.
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“Data from mouse models of HLH and patients with cytokine storm indicate that the inability of CTLs to kill efficiently leads to prolonged activation of T cells, triggering a cascade of inflammatory tissue damage.”
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Cites
SIFT: predicting amino acid changes that affect protein function
Ng, P. C. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg509 · Cited by 6,601
Amino Acid Difference Formula to Help Explain Protein Evolution
Grantham, R. L. (1974) · Science · doi:10.1126/science.185.4154.862 · Cited by 2,363
Human non-synonymous SNPs: server and survey
Ramensky, V. E. (2002) · Nucleic Acids Research · doi:10.1093/nar/gkf493 · Cited by 2,299
Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis
Stepp, S. E., Dufourcq-Lagelouse, R., Deist, F. L., Bhawan, S., Dogniaux, S., Mathew, P. A., Henter, J., Bennett, M., Fischer, A., Basile, G. D. S., et al. (1999) · Science · doi:10.1126/science.286.5446.1957 · Cited by 1,236
Feldmann, J., Callebaut, I., Raposo, G., Dogniaux, S., Bacq, D., Dumont, C., Lambert, N., Ouachée-Chardin, M., Chédeville, G., Tamary, H., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00855-9 · Cited by 935
XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome
Rigaud, S., Fondanèche, M., Lambert, N., Pasquier, B., Mateo, V., Soulas-Sprauel, P., Galicier, L., Deist, F. L., Rieux‐Laucat, F., Revy, P., et al. (2006) · Nature · doi:10.1038/nature05257 · Cited by 703
Stadt, U. Z. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi076 · Cited by 559
Aricò, M., Janka, G., Fischer, A., Henter, J., Blanche, S., Elinder, G., Martinetti, M., & Rusca, M. P. (1996) · PubMed · Cited by 468
Stadt, U. Z., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauß, J., Kasper, B., Nürnberg, G., Becker, C., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.09.005 · Cited by 421
Hemophagocytic lymphohistiocytosis (HLH) and related disorders
Filipovich, A. H. (2009) · Hematology · doi:10.1182/asheducation-2009.1.127 · Cited by 400
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Yu, W., Wu, Y., Duan, W.-B., Chen, Q., Pei, X., Jia, J., Wang, J., Zhu, X., Zhao, X., Huang, X., et al. (2025) · Immuno · doi:10.3390/immuno5040058
Zhang, J., Sun, Y., Xiaodong, S., Zhang, R., Wang, Y., Xiao, J., Cao, J., Gao, Z., Wang, J., Wu, L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.12262871
Liu, C., Liu, W., Ding, Y., Liu, X., & Liu, S. (2026) · Future Virology · doi:10.1080/17460794.2026.2620962
Chauhan, P., Singh, C., Bhatia, P., Sharma, S., Jandial, A., Jain, A., Prakash, G., Khadwal, A., Rawat, A., Das, R., et al. (2026) · Indian Journal of Hematology and Blood Transfusion · doi:10.1007/s12288-026-02359-x
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Sagawa, H., Hirata, K., Katayama, S., Shibata, H., Toyofuku, E., Kaneko, S., Katata, Y., Takezawa, Y., Uematsu, M., Onishi, I., et al. (2026) · Journal of Clinical Immunology · doi:10.1007/s10875-026-01988-1
Almaalouli, B., Smith, H., Kirsch, G., Courant, V., & Kaeley, G. S. (2026) · Cureus · doi:10.7759/cureus.106267
Fauteux‐Daniel, S. (2018) · theses.fr (ABES) · doi:10.70675/e5b20efbzd517z4af5z92a9z60598ef91d59
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Merz, L. E., & Berliner, N. (2026) · Springer eBooks · doi:10.1007/978-3-032-13858-3_55
Amikishiyev, S., Deniz, R., Günver, M. G., Aghamuradov, S., Koca, N., İnce, B., Bektaş, M., Yilmaz, A., Cantürk, Y., Durak, G., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1722572
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Grom, A. A., & Schulert, G. S. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-11980-4.00048-9
Thangaraj, A., Aggarwal, R., Sarkar, S., & Pilania, R. K. (2026) · World Journal of Clinical Pediatrics · doi:10.5409/wjcp.118174
Hemophagocytic lymphohistiocytosis - when an exaggerated immune response escapes control mechanisms
Machaczka, M., & Klimkowska, M. (2013) · MedCaseReports · doi:10.67417/medcasereports.45
Dierks, F., Paulsen, F., Lehmberg, K., Rosenwald, A., Bokemeyer, C., Weisel, K., & Seidel, C. A. (2026) · Annals of Hematology · doi:10.1007/s00277-026-07177-9
孙, 亚. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.1693054
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Díaz, M. A. T. (2026) · IntechOpen eBooks · doi:10.5772/intechopen.1015478
Vachon, E. A., Jain, H. B., & Kitten, S. (2026) · Case Reports in Rheumatology · doi:10.1155/crrh/9165820
Lorenzini, T., Sabet, O., Chazli, Y. E., Soomann, M., & Schmid, J. P. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.2017167
Metadata
- Authors
- Zhang, K., Jordan, M. B., Marsh, R. A., Johnson, J. A., Kissell, D., Meller, J., Villanueva, J., Risma, K. A., Wei, Q., Klein, P. S., & Filipovich, A. H.
- Affiliations
- Division of Human Genetics,
- Division of Immunobiology,
- Division of Bone Marrow Transplant and Immune Deficiency,
- Department of Environmental Health and Biomedical Engineering,
- Diagnostic Immunology Laboratory, and
- Cincinnati Children's Hospital Medical Center (US)
- Duke University (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-11-24
- Volume
- 118
- Issue
- 22
- Pages
- 5794-5798
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3228496
- OpenAlex
- W2013522127
- Cited by
- 428
- References
- 36
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 25 · 2023: 26 · 2022: 30 · 2021: 31 · 2020: 37 · 2019: 32 · 2018: 25 · 2017: 32 · 2016: 28 · 2015: 45 · 2014: 35 · 2013: 21 · 2012: 16
- FWCI
- 16.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Histiocytosis Association
- National Heart, Lung, and Blood Institute (R01HL091769, HL091769)
- Topics
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- familial hemophagocytic lymphohistiocytosis, adult-onset HLH, PRF1, Munc13-4, STXBP2, hypomorphic mutation, missense mutations, splice site mutation, primary immunodeficiency, late-onset disease
- MeSH terms
- Adolescent, Adult, Aged, DNA Mutational Analysis, Female, Gene Frequency, Humans, Male, Membrane Proteins, Middle Aged, Mutation, Age of Onset, Lymphohistiocytosis, Hemophagocytic, Munc18 Proteins, Pore Forming Cytotoxic Proteins, Perforin, Young Adult
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