Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype
Julie Toubiana, Satoshi Okada, Julia Hiller, Matias Oleastro, Macarena Lagos Gomez, Juan Carlos Aldave Becerra, Marie Ouachée-Chardin, Fanny Fouyssac, Katta Mohan Girisha, Amos Etzioni, Joris Van Montfrans, Yildiz Camcioglu, Leigh Ann Kerns, Bernd Belohradsky, Stéphane Blanche, Aziz Bousfiha, Carlos Rodriguez-Gallego, Isabelle Meyts, Kai Kisand, Janine Reichenbach, Ellen D Renner, Sergio Rosenzweig, Bodo Grimbacher, Frank L van de Veerdonk, Claudia Traidl-Hoffmann, Capucine Picard, Laszlo Marodi, Tomohiro Morio, Masao Kobayashi, Desa Lilic, Joshua D Milner, Steven Holland, Jean-Laurent Casanova, Anne Puel, International STAT1 Gain-of-Function Study Group, Sophie Cypowyj, Caroline Thumerelle, Antoine Toulon, Jacinta Bustamante, Natalia Tahuil, Aicha Salhi, Sorina Boiu, Charu Chopra, Daniela Di Giovanni, Liliana Bezrodnik, Jeannette Boutros, Caroline Thomas, Gina Lacuesta, Sarah Jannier, Anne-Sophie Korganow, Catherine Paillard, David Boutboul, Mélanie Bué, Aude Marie-Cardine, Sophie Bayart, Mélanie Migaud, Laurence Weiss, Marina Karmochkine, Juan-Miguel Garcia-Martinez, Jean-Louis Stephan, Philippe Bensaid, Guy-Patrick Jeannoel, Torsten Witte, Ulrich Baumann, Thomas Harrer, Carmen Navarrete, Antony Terance Benjamin, Davide Firinu, Claudio Pignata, Paolo Picco, David Mendoza, Saul Oswaldo Lugo Reyes, Carlos Torres Lozano, Margarita Ortega-Cisneros, Mariana Cortina, Mehrnaz Mesdaghi, Mohammad Nabavi, Teresa Español, Maía Teresa Martínez-Saavedra, Nima Rezaei, Samaneh Zoghi, Malgorzata Pac, Vincent Barlogis, Gabriel Revon-Rivière, Yishai Haimi-Cohen, Ronen Spiegel, Dan Miron, Jabir Bouchaib, Lizbeth Blancas-Galicia, Beata Toth, Barbara Drexel, Pierre Simon Rohrlich, Olivier Lesens, Miriam Hoernes, Elizabeth Drewe, Mario Abinum, Julie Sawalle-Belohradsky, Gerhard Kindle, Mark Depner, Lili Milani, Tiit Nikopensius, Maido Remm, Ulvi Gerst Talas, Mark Tucker, Mary Willis, Stephanie Leonard, Hilaire Meuwissen, Ronald M. Ferdman, Mark Wallace, Mukesh M. Desai, Prasad Taur, Raffaele Badolato, Beata Soltesz, Christina Schnopp, Annette F. Jansson, Deniz Ayvaz, Nadejda Shabashova, Liudmyla Chernyshova, Anastasia Bondarenko, Despina Moshous, Benedicte Neven, Chahinez Boubidi, Fatima Ailal, Giuliana Giardino, Stefano Del Giacco, Marie-Elisabeth Bougnoux, Kohsuke Imai, Teppei Okawa, Yoko Mizoguchi, Yusuke Ozaki, Masato Takeuchi, Akira Hayakawa, Birgit Lögering, Kristian Reich, Timo Buhl, Kilian Eyerich, Martin Schaller, Peter D. Arkwright, Andrew R. Gennery, Andrew J. Cant, Adilia Warris, Stefanie Henriet, Najla Mekki, Ridha Barbouche, Imen Ben Mustapha, Christine Bodemer, Michel Polak, Emmanuel Grimprel, Pierre-Régis Burgel, Alain Fischer, Olivier Hermine, Marianne Debré, Dilara Kocacyk, Fatima Dhalla, Smita Y. Patel, Leen Moens, Filomeen Haerynck, Melissa Dullaers, Levi Hoste, Ozden Sanal, Sara Sebnem Kilic, Joachim Roesler, Fanny Lanternier, Olivier Lortholary, Claire Fieschi, Joseph A. Church, Chaim Roifman, Araya Yuenyongviwat, Pärt Peterson, Stéphanie Boisson-Dupuis, Laurent Abel, Beatriz E. Marciano, Mihai G. Netea, Julie Toubiana, Satoshi Okada, Julia Hiller, Matias Oleastro, Macarena Lagos Gomez, Juan Carlos Aldave Becerra, Marie Ouachée-Chardin, Fanny Fouyssac, Katta Mohan Girisha, Amos Etzioni, Joris Van Montfrans, Yildiz Camcioglu, Leigh Ann Kerns, Bernd Belohradsky, Stéphane Blanche, Aziz Bousfiha, Carlos Rodriguez-Gallego, Isabelle Meyts, Kai Kisand, Janine Reichenbach, Ellen D Renner, Sergio Rosenzweig, Bodo Grimbacher, Frank L van de Veerdonk, Claudia Traidl-Hoffmann, Capucine Picard, Laszlo Marodi, Tomohiro Morio, Masao Kobayashi, Desa Lilic, Joshua D Milner, Steven Holland, Jean-Laurent Casanova, Anne Puel, International STAT1 Gain-of-Function Study Group, Sophie Cypowyj, Caroline Thumerelle, Antoine Toulon, Jacinta Bustamante, Natalia Tahuil, Aicha Salhi, Sorina Boiu, Charu Chopra, Daniela Di Giovanni, Liliana Bezrodnik, Jeannette Boutros, Caroline Thomas, Gina Lacuesta, Sarah Jannier, Anne-Sophie Korganow, Catherine Paillard, David Boutboul, Mélanie Bué, Aude Marie-Cardine, Sophie Bayart, Mélanie Migaud, Laurence Weiss, Marina Karmochkine, Juan-Miguel Garcia-Martinez, Jean-Louis Stephan, Philippe Bensaid, Guy-Patrick Jeannoel, Torsten Witte, Ulrich Baumann, Thomas Harrer, Carmen Navarrete, Antony Terance Benjamin, Davide Firinu, Claudio Pignata, Paolo Picco, David Mendoza, Saul Oswaldo Lugo Reyes, Carlos Torres Lozano, Margarita Ortega-Cisneros, Mariana Cortina, Mehrnaz Mesdaghi, Mohammad Nabavi, Teresa Español, Maía Teresa Martínez-Saavedra, Nima Rezaei, Samaneh Zoghi, Malgorzata Pac, Vincent Barlogis, Gabriel Revon-Rivière, Yishai Haimi-Cohen, Ronen Spiegel, Dan Miron, Jabir Bouchaib, Lizbeth Blancas-Galicia, Beata Toth, Barbara Drexel, Pierre Simon Rohrlich, Olivier Lesens, Miriam Hoernes, Elizabeth Drewe, Mario Abinum, Julie Sawalle-Belohradsky, Gerhard Kindle, Mark Depner, Lili Milani, Tiit Nikopensius, Maido Remm, Ulvi Gerst Talas, Mark Tucker, Mary Willis, Stephanie Leonard, Hilaire Meuwissen, Ronald M. Ferdman, Mark Wallace, Mukesh M. Desai, Prasad Taur, Raffaele Badolato, Beata Soltesz, Christina Schnopp, Annette F. Jansson, Deniz Ayvaz, Nadejda Shabashova, Liudmyla Chernyshova, Anastasia Bondarenko, Despina Moshous, Benedicte Neven, Chahinez Boubidi, Fatima Ailal, Giuliana Giardino, Stefano Del Giacco, Marie-Elisabeth Bougnoux, Kohsuke Imai, Teppei Okawa, Yoko Mizoguchi, Yusuke Ozaki, Masato Takeuchi, Akira Hayakawa, Birgit Lögering, Kristian Reich, Timo Buhl, Kilian Eyerich, Martin Schaller, Peter D. Arkwright, Andrew R. Gennery, Andrew J. Cant, Adilia Warris, Stefanie Henriet, Najla Mekki, Ridha Barbouche, Imen Ben Mustapha, Christine Bodemer, Michel Polak, Emmanuel Grimprel, Pierre-Régis Burgel, Alain Fischer, Olivier Hermine, Marianne Debré, Dilara Kocacyk, Fatima Dhalla, Smita Y. Patel, Leen Moens, Filomeen Haerynck, Melissa Dullaers, Levi Hoste, Ozden Sanal, Sara Sebnem Kilic, Joachim Roesler, Fanny Lanternier, Olivier Lortholary, Claire Fieschi, Joseph A. Church, Chaim Roifman, Araya Yuenyongviwat, Pärt Peterson, Stéphanie Boisson-Dupuis, Laurent Abel, Beatriz E. Marciano, Mihai G. Netea
Abstract
Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guérin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.
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Source: PubMed