{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T19:38:41Z","timestamp":1754163521850,"version":"3.41.2"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Human herpesvirus 6B (HHV-6B) is associated with various central nervous system (CNS) disorders, particularly in immunocompromised patients. We present a rare case of inherited chromosomally integrated HHV-6B (iciHHV-6B), also referred to as endogenous HHV-6B (eHHV-6B) discovered during the workup for encephalitis in a child with relapsed non-WNT\/non-SHH medulloblastoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case presentation<\/jats:title><jats:p>A preschool aged female was treated in infancy for non-WNT, non-SHH medulloblastoma with high dose chemotherapy and autologous stem cell transplant. She had leptomeningeal recurrence 6 months after transplant and received salvage therapy with high dose craniospinal proton therapy. Six months following radiation, she developed high fever, acute encephalopathy and seizures. Neuroimaging revealed left posterior temporal gyral edema, while extensive infectious\/paraneoplastic\/autoimmune workup demonstrated markedly elevated HHV-6B viral loads, consistent with inherited chromosomally integrated HHV-6B (iciHHV-6B) which was confirmed through blood digital droplet PCR analysis and PCR-based nail clipping analysis demonstrating paternal inheritance. Retrospective immunohistochemical analysis of the original medulloblastoma revealed HHV-6 late structural glycoprotein H antigens in peritumoral lymphocytes. Serum HHV-6 U100 glycoprotein mRNA detection was consistent with iciHHV-6B. Treatment included intravenous immunoglobulin (IVIG) and ganciclovir followed by a 12-month course of IVIG monotherapy with clinical improvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our case highlights the diagnostic challenges, controversies and clinical implications of ici-HHV-6\/eHHV-6 in immunocompromised patients with encephalitis, where qualitative CSF viral detection alone may be insufficient for accurate diagnosis and cannot identify ici-HHV-6 status which complicates treatment decisions. This case demonstrates the importance of multimodal testing including chromosomal integration analysis in patients with high HHV-6 viral loads.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1615359","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T05:38:32Z","timestamp":1753940312000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Inherited chromosomally integrated HHV-6B in a pediatric medulloblastoma patient with encephalitis"],"prefix":"10.3389","volume":"16","author":[{"given":"Scott","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstance","family":"Knox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Romashko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhu","family":"Kundu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiying","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meei-Li","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise M.","family":"Malicki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John R.","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e180","DOI":"10.1371\/journal.pmed.0040180","article-title":"Association of human herpesvirus-6B with mesial temporal lobe epilepsy","volume":"4","author":"Fotheringham","year":"2007","journal-title":"PloS Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2012.04.033","article-title":"Chromosomally-integrated human herpesvirus 6 in familial glioma etiology","volume":"79","author":"Amirian","year":"2012","journal-title":"Med Hypotheses"},{"key":"B3","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/B978-0-444-62703-2.00018-5","article-title":"Chapter 18 - HHV-6A and HHV-6B in cancer","volume-title":"Human herpesviruses HHV-6A, HHV-6B & HHV-7","author":"Crawford","year":"2014"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00122-14","article-title":"Laboratory and clinical aspects of human herpesvirus 6 infections","volume":"28","author":"Agut","year":"2015","journal-title":"Clin Microbiol Rev"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-013-1902-5","article-title":"Classification of HHV-6A and HHV-6B as distinct viruses","volume":"159","author":"Ablashi","year":"2014","journal-title":"Arch Virol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/v9070194","article-title":"Latency, integration, and reactivation of human herpesvirus-6","volume":"9","author":"Pantry","year":"2017","journal-title":"Viruses"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.52.8.620","article-title":"Detection of human herpesviruses 6 and 7 genomic sequences in brain tumours","volume":"52","author":"Chan","year":"1999","journal-title":"J Clin Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.20113","article-title":"Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA","volume":"73","author":"Tanaka-Taya","year":"2004","journal-title":"J Med Virol"},{"key":"B9","article-title":"Chapter 16 - Human herpesvirus 6 and the nervous system","volume-title":"Handbook of clinical neurology","author":"Hill","year":"2014"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.1890470119","article-title":"Human herpesvirus-6: a survey of presence and distribution of genomic sequences in normal brain and neuroglial tumors","volume":"47","author":"Luppi","year":"1995","journal-title":"J Med Virol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2012.03494.x","article-title":"Symptomatic generalized epilepsy after HHV6 posttransplant acute limbic encephalitis in children","volume":"53","author":"Howell","year":"2012","journal-title":"Epilepsia"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv162","article-title":"Human herpesvirus 6 as a viral trigger in mesial temporal lobe epilepsy","volume":"212","author":"Leibovitch","year":"2015","journal-title":"J Infect Diseases"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1017\/s0012162200000773","article-title":"Human herpesvirus-6 associated encephalitis with subsequent infantile spasms and cerebellar astrocytoma","volume":"42","author":"Rantala","year":"2000","journal-title":"Dev Med Child Neurol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv160","article-title":"Pathogenic role of human herpesvirus 6B infection in mesial temporal lobe epilepsy","volume":"212","author":"Kawamura","year":"2015","journal-title":"J Infect Diseases"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2217\/fvl-2021-0096","article-title":"Association between human herpesvirus-6 and primary brain tumors: a systematic review and meta-analysis","volume":"17","author":"Ghorbani","year":"2022","journal-title":"Future Virology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.jcv.2009.05.011","article-title":"Detection of human herpesvirus-6 variants in pediatric brain tumors: association of viral antigen in low grade gliomas","volume":"46","author":"Crawford","year":"2009","journal-title":"J Clin Virol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s11060-009-9908-2","article-title":"Detection of human herpesvirus-6 in adult central nervous system tumors: predominance of early and late viral antigens in glial tumors","volume":"95","author":"Crawford","year":"2009","journal-title":"J Neurooncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.715","article-title":"Chromosomally integrated human herpesvirus 6: questions and answers","volume":"22","author":"Pellett","year":"2012","journal-title":"Rev Med Virol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.23685","article-title":"Persistent human herpesvirus-6 infection in patients with an inherited form of the virus","volume":"85","author":"Pantry","year":"2013","journal-title":"J Med Virol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"vi1","DOI":"10.1093\/neuonc\/noae145","article-title":"CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2017-2021","volume":"26","author":"Price","year":"2024","journal-title":"Neuro Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-009-0080-z","article-title":"Seizures and epilepsy in cancer patients","volume":"10","author":"Avila","year":"2010","journal-title":"Curr Neurol Neurosci Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jis513","article-title":"Human herpesvirus 6 latent infection in patients with glioma","volume":"206","author":"Chi","year":"2012","journal-title":"J Infect Dis"},{"key":"B23","unstructured":"HHV-6 tissue immunohistochemistry (IHC)\n          \n          \n          2023"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01419-18","article-title":"RNA sequencing of the in vivo human herpesvirus 6B transcriptome to identify targets for clinical assays distinguishing between latent and active infection","volume":"93","author":"Hill","year":"2019","journal-title":"J Virol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.02016-18","article-title":"The brief case: inherited chromosomally integrated human herpesvirus 6 (HHV-6) in the age of multiplex HHV-6 testing","volume":"57","author":"Greninger","year":"2019","journal-title":"J Clin Microbiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2013.217240","article-title":"Identification of chromosomally integrated human herpesvirus 6 by droplet digital PCR","volume":"60","author":"Sedlak","year":"2014","journal-title":"Clin Chem"},{"key":"B27","unstructured":"HHV-6 chromosomal integration (ci-HHV-6)\n          \n          \n          2022"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.44.4.1571-1574.2006","article-title":"Human herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, sera, and hair follicles","volume":"44","author":"Ward","year":"2006","journal-title":"J Clin Microbiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu323","article-title":"Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency","volume":"59","author":"Endo","year":"2014","journal-title":"Clin Infect Dis"},{"key":"B30","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.jcv.2017.11.004","article-title":"Radiotherapy-induced reactivation of neurotrophic human herpes viruses: Overview and management","volume":"98","author":"Ramirez-Fort","year":"2018","journal-title":"J Clin Virol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004033","article-title":"Reactivation of chromosomally integrated human herpesvirus-6 by telomeric circle formation","volume":"9","author":"Prusty","year":"2013","journal-title":"PloS Genet"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2022-056759","article-title":"Persistent HHV-6 DNAemia in a patient presenting with meningoencephalitis","volume":"150","author":"Sandhu","year":"2022","journal-title":"Pediatrics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/ana.26549","article-title":"Cerebral cortical encephalitis in myelin oligodendrocyte glycoprotein antibody-associated disease","volume":"93","author":"Valencia-Sanchez","year":"2023","journal-title":"Ann Neurol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"578283","DOI":"10.1016\/j.jneuroim.2024.578283","article-title":"Inherited chromosomally-integrated human herpes virus 6 confounding test results in a patient with myelitis and optic neuritis - A case report","volume":"387","author":"Tan","year":"2024","journal-title":"J Neuroimmunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"577521","DOI":"10.1016\/j.jneuroim.2021.577521","article-title":"COVID-19, HHV6 and MOG antibody: A perfect storm","volume":"353","author":"Jumah","year":"2021","journal-title":"J Neuroimmunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1615359\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T05:38:34Z","timestamp":1753940314000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1615359\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,31]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2025.1615359"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1615359","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2025,7,31]]},"article-number":"1615359"}}