Ghosh, SujalBal, Sevgi KöstelEdwards, Emily S JPillay, BethanyJimenez-Heredia, RaúlRao, GeethaErol Çipe, FundaSalzer, ElisabethZoghi, SamanehAbolhassani, HassanMomen, ToobaGostick, EmmaPrice, David AZhang, YuOler, Andrew JGonzaga-Jauregui, ClaudiaErman, BaranMetin, Ayşeİlhan, İnciHaskoloğlu, Şuleİslamoğlu, CandanBaskın, KübraCeylaner, SerdarYılmaz, EbruÜnal, EkremKarakukcu, MusaBerghuis, DagmarCole, TheresaGupta, Aditya KumarHauck, FabianHoepelman, AndyBarış, SafaKarakoç Aydıner, ElifÖzen, AhmetKager, LeoHolzinger, DirkPaulussen, MichaelKrüger, RenateMeisel, RolandOommen, Prasad ThomasMorris, Emma CNeven, BenedicteWorth, Austen J JMontfrans, Joris M vanFraaij, PieterChoo, SharonDoğu, FigenDavies, E GrahamBurns, SiobhanDueckers, GregorBecker, Ruy PerezBernuth, Horst vonLatour, SylvainFaraci, MauraGattorno, MarcoSu, HelenPan-Hammarström, QiangHammarström, LennartLenardo, Michael JMa, Cindy SNiehues, TimAghamohammadi, AsgharRezaei, NimaIkinciogullari, AydanTangye, Stuart GLankester, Arjan CBoztuğ, Kaan2020-09-222020-09-222020Ghosh, S., Köstel Bal, S., Edwards, E. S., Pillay, B., Jimenez-Heredia, R., Rao, G., ... & Momen, T. (2020). Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency. Blood.https://doi.org/10.1182/blood.2020006738https://hdl.handle.net/20.500.12713/1070Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural history, immune characteristics and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected clinical information of 49 patients from 29 families (CD27 n=33, CD70 n=16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority (90%) of patients were EBV+ at diagnosis, but only ~30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one (43%) patients developed autoinflammatory features including uveitis, arthritis and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.eninfo:eu-repo/semantics/openAccessArticle32603431WOS:0005996455000102-s2.0-85089514359Q110.1182/blood.2020006738N/A