Cited by 428Autoimmune and Inflammatory Disorders ResearchImmunodeficiency and Autoimmune DisordersInflammasome and immune disorders

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Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH

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Zhang, Kejian, Jordan, Michael B., Marsh, Rebecca A., Johnson, Judith A., Kissell, Diane, Meller, Jarek, Villanueva, Joyce, Risma, Kimberly A., Wei, Qian, Klein, Peter S., Filipovich, Alexandra H.·2011·Blood

DOI 10.1182/blood-2011-07-370148PMC PMC3228496

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Abstract

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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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: Zhang, Kejian
Jordan, Michael B.
Marsh, Rebecca A.
Meller, Jarek
Risma, Kimberly A.
Wei, Qian
Klein, Peter S.
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
DOI: 10.1182/blood-2011-07-370148
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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Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH

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