Abstract:
:Bi-allelic null mutations affecting UNC13D, STXBP2, or STX11 result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL) in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of this disease, or with HLH later in life. Here, we studied two sisters with lymphocyte degranulation defects secondary to compound heterozygote missense variants in UNC13D. The older sibling presented aged 11 with linear growth arrest and delayed puberty, 2 years prior to developing transient ischemic attacks secondary to neuroinflammation and hypogammaglobulinemia, but no FHL symptoms. Her geno-identical younger sister was initially asymptomatic but then presented at the same age with severe EBV-driven infectious mononucleosis, which was treated aggressively and did not progress to HLH. The sisters had similar natural killer cell degranulation; however, while cytotoxic activity was moderately reduced in the asymptomatic patient, it was completely absent in both siblings during active disease. Following allogeneic bone marrow transplantation at the age of 15, the older child has completely recovered NK cell cytotoxicity, is asymptomatic, and has experienced an exceptional compensatory growth spurt. Her younger sister was also successfully transplanted and is currently disease free. The current study reveals previously unappreciated manifestations of FHL in patients who inherited hypomorphic gene variants and also raises the important question of whether a threshold of minimum NK function can be defined that should protect a patient from serious disease manifestations such as HLH.
journal_name
Front Immunoljournal_title
Frontiers in immunologyauthors
Gray PE,Shadur B,Russell S,Mitchell R,Buckley M,Gallagher K,Andrews I,Thia K,Trapani JA,Kirk EP,Voskoboinik Idoi
10.3389/fimmu.2017.00944subject
Has Abstractpub_date
2017-08-09 00:00:00pages
944issn
1664-3224journal_volume
8pub_type
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.3389/fimmu.2020.583338
更新日期:2020-12-16 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章,评审
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2020-06-09 00:00:00
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journal_title:Frontiers in immunology
pub_type: 已发布勘误
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更新日期:2016-04-28 00:00:00
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pub_type: 杂志文章,评审
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pub_type: 杂志文章,评审
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