Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH
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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.
“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.”
From Cytokine storm (2020) · cites this paper as [22]
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- 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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