Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D
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 alter...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00944/full |
| _version_ | 1818304379650834432 |
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| author | Paul Edgar Gray Bella Shadur Susan Russell Richard Mitchell Michael Buckley Kerri Gallagher Ian Andrews Kevin Thia Joseph A. Trapani Edwin Philip Kirk Ilia Voskoboinik |
| author_facet | Paul Edgar Gray Bella Shadur Susan Russell Richard Mitchell Michael Buckley Kerri Gallagher Ian Andrews Kevin Thia Joseph A. Trapani Edwin Philip Kirk Ilia Voskoboinik |
| author_sort | Paul Edgar Gray |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T06:09:46Z |
| format | Article |
| id | doaj.art-9b1fec07a2704ab881fd21c60040f714 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T06:09:46Z |
| publishDate | 2017-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9b1fec07a2704ab881fd21c60040f7142022-12-21T23:57:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-08-01810.3389/fimmu.2017.00944292033Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13DPaul Edgar Gray0Bella Shadur1Susan Russell2Richard Mitchell3Michael Buckley4Kerri Gallagher5Ian Andrews6Kevin Thia7Joseph A. Trapani8Edwin Philip Kirk9Ilia Voskoboinik10Department of Immunology and Infectious Diseases, Sydney Children’s Hospital, Randwick, NSW, AustraliaDepartment of Immunology and Infectious Diseases, Sydney Children’s Hospital, Randwick, NSW, AustraliaKids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, AustraliaKids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, AustraliaGenetics Laboratory, South Eastern Area Laboratory Services, Randwick, NSW, AustraliaDepartment of Immunology, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaDepartment of Neurology, Sydney Children’s Hospital, Randwick, NSW, AustraliaCancer Cell Death Laboratory, Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne VIC, AustraliaCancer Cell Death Laboratory, Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne VIC, AustraliaCentre for Clinical Genetics, Sydney Children’s Hospital, Randwick, NSW, AustraliaKiller Cell Biology Laboratory, Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, VIC, AustraliaBi-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.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00944/fullcytotoxic lymphocytesHLHimmunodeficiencyhematologypathology |
| spellingShingle | Paul Edgar Gray Bella Shadur Susan Russell Richard Mitchell Michael Buckley Kerri Gallagher Ian Andrews Kevin Thia Joseph A. Trapani Edwin Philip Kirk Ilia Voskoboinik Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D Frontiers in Immunology cytotoxic lymphocytes HLH immunodeficiency hematology pathology |
| title | Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D |
| title_full | Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D |
| title_fullStr | Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D |
| title_full_unstemmed | Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D |
| title_short | Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D |
| title_sort | late onset non hlh presentations of growth arrest inflammatory arachnoiditis and severe infectious mononucleosis in siblings with hypomorphic defects in unc13d |
| topic | cytotoxic lymphocytes HLH immunodeficiency hematology pathology |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00944/full |
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