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Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

2020; Elsevier BV; Volume: 146; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2019.11.051

1097-6825

Tiziana Lorenzini, Manfred Fliegauf, Nils Klammer, Natalie Frede, Michele Proietti, Alla Bulashevska, Nadezhda Camacho-Ordóñez, Markku Varjosalo, Matias Kinnunen, Esther de Vries, J.W.M. van der Meer, Rohan Ameratunga, Chaim M. Roifman, Yael Dinur Schejter, Robin Kobbe, Timo Hautala, Faranaz Atschekzei, Reinhold E. Schmidt, Claudia Schröder, Polina Stepensky, Bella Shadur, Luis Alberto Pedroza, Michiel van der Flier, Mónica Martínez‐Gallo, Luis Ignacio González‐Granado, Luís M. Allende, Anna Shcherbina, N. B. Kuzmenko, V.P. Zakharova, João Farela Neves, Peter Švec, Ute Fischer, Winnie Ip, Oliver Bartsch, Safa Barış, Christoph Klein, Raif S. Geha, Janet Chou, Mohammed F. Alosaimi, Lauren Weintraub, Kaan Boztuğ, Tatjana Hirschmugl, Maria Marluce dos Santos Vilela, Dirk Holzinger, Maximilian Seidl, Vassilios Lougaris, Alessandro Plebani, Laia Alsina, M. Piquer‐Gibert, Àngela Deyà‐Martínez, C Slade, Asghar Aghamohammadi, Hassan Abolhassani, Lennart Hammarström, Outi Kuismin, Merja Helminen, Hana Lango Allen, James E. Thaventhiran, Alexandra F. Freeman, Matthew Cook, Shahrzad Bakhtiar, Mette Christiansen, Charlotte Cunningham‐Rundles, Niraj Patel, William Rae, Tim Niehues, Nina Brauer, Jaana Syrjänen, Mikko Seppänen, Siobhan O. Burns, Paul Tuijnenburg, Taco W. Kuijpers, Klaus Warnatz, Bodo Grimbacher, Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William J. Astle, Anthony Attwood, Chiara Bacchelli, Joana Batista, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Marta Bleda, Barbara Boardman, Claire Booth, John R. Bradley, Gerome Breen, Matthew A. Brown, Michael J. Browning, Mary Brownlie, Matthew Buckland, Siobhan O. Burns, Oliver S. Burren, Keren Carss, John C. Chambers, Anita Chandra, Naomi Clements Brod, Hayley Clifford, Nichola Cooper, Louise C. Daugherty, E. Graham Davies, Sophie Davies, John M. Davis, Sarah Deacock, Sri V. V. Deevi, John Dempster, Lisa Devlin, Eleanor Dewhurst, Kate Downes, Elizabeth Drewe, Daniel Duarte, David Edgar, Karen L. Edwards, William Egner, Tariq El‐Shanawany, Marie Erwood, Debra Fletcher, James W. Fox, Amy Frary, Mattia Frontini, Abigail Furnell, H. Bobby Gaspar, Rohit Ghurye, Kimberly Gilmour, Nicholas Gleadall, Sarah Goddard, Pavels Gordins, Stefan Gräf, Luigi Grassi, Daniel Greene, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Matthias Haimel, Lorraine Harper, Grant Hayman, Archana Herwadkar, Fengyuan Hu, Stephen Hughes, Aarnoud Huissoon, Roger James, Stephen Jolles, Jennifer Jolley, Julie R. Jones, Mohammed Yousuf Karim, Mary Kasanicki, Peter Kelleher, Carly Kempster, Sorena Kiani, Nathalie Kingston, Nigel Klein, Myrto Kostadima, Roman Kreuzhuber, Taco W. Kuijpers, Dinakantha Kumararatne, James Laffan, Hana Lango Allen, Sara Lear, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Paul Lyons, Jesmeen Maimaris, Ania Manson, Rutendo Mapeta, Jennifer M. Martin, Mark I. McCarthy, Elizabeth McDermott, Harriet McKinney, Stuart Meacham, Karyn Mégy, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Christopher J. Penkett, R. Petersen, Mark Ponsford, Waseem Qasim, Ellie Quinn, Isabella Quinti, F. Lucy Raymond, Paula Rayner-Matthews, Alex Richter, Nilesh J. Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar Sargur, Sinisa Savic, Suranjith L. Seneviratne, William A. Sewell, Denis Seyres, Fiona Shackley, Olga Shamardina, Ilenia Simeoni, Michael A. Simpson, Kenneth G. C. Smith, Simon Staines, Emily Staples, Hannah Stark, Hans J. Stauss, Cathal Steele, Jonathan Stephens, Kathleen Stirrups, James E. Thaventhiran, David Y. Thomas, Moira Thomas, Patrick Thomas, Adrian J. Thrasher, Tobias Tilly, Catherine Titterton, Paul Treadaway, Salih Tuna, Ernest Turro, Rafał Urniaż, Julie von Ziegenweidt, N. P. J. Walker, Christopher D. Watt, Steven B. Welch, Deborah Whitehorn, Lisa Willcocks, Nicholas Wood, Yvette Wood, Sarita Workman, Austen Worth, Katherine Yates, Nigel Yeatman, Patrick Yong, Timothy J. Young, Ping Yu, Eliska Zlamalova,

interferon and immune responses

An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes.To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling.We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents.We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.