Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype
Date
2016Author
van de Veerdonk, Frank L.
Kisand, Kai
Reichenbach, Janine
Renner, Ellen D.
Rosenzweig, Sergio
Grimbacher, Bodo
Traidl-Hoffmann, Claudia
Picard, Capucine
Marodi, Laszlo
Morio, Tomohiro
Kobayashi, Masao
Lilic, Desa
Milner, Joshua D.
Holland, Steven
Casanova, Jean-Laurent
Puel, Anne
Cypowyj, Sophie
Thumerelle, Caroline
Toulon, Antoine
Bustamante, Jacinta
Tahuil, Natalia
Salhi, Aicha
Boiu, Sorina
Chopra, Charu
Di Giovanni, Daniela
Bezrodnik, Liliana
Boutros, Jeannette
Thomas, Caroline
Lacuesta, Gina
Jannier, Sarah
Camcioglu, Yildiz
Bue, Melanie
Marie-Cardine, Aude
Bayart, Sophie
Migaud, Melanie
Weiss, Laurence
Karmochkine, Marina
Garcia-Martinez, Juan-Miguel
Stephan, Jean-Louis
Bensaid, Philippe
Jaennoel, Guy-Patrick
Witte, Torsten
Baumann, Ulrich
Harrer, Thomas
Navarrete, Carmen
Benjamin, Antony Terance
Firinu, Davide
Pignata, Claudio
Picco, Paolo
Mendoza, David
Reyes, Saul Oswaldo Lugo
Lozano, Carlos Torres
Ortega-Cisneros, Margarita
Cortina, Mariana
Mesdaghi, Mehrnaz
Nabavi, Mohammad
Espanol, Teresa
Martinez-Saavedra, Maia Teresa
Rezaei, Nima
Zoghi, Samaneh
Pac, Malgorzata
Barlogis, Vincent
Revon-Riviere, Gabriel
Haimi-Cohen, Yishai
Spiegel, Ronen
Miron, Dan
Bouchaib, Jabir
Blancas-Galicia, Lizbeth
Toth, Beata
Drexel, Barbara
Rohrlich, Pierre Simon
Lesens, Olivier
Hoernes, Miriam
Drewe, Elizabeth
Abinum, Mario
Sawalle-Belohradsky, Julie
Kindle, Gerhard
Depner, Mark
Milani, Lili
Nikopensius, Tiit
Remm, Maido
Talas, Ulvi Gerst
Tucker, Mark
Willis, Mary
Leonard, Stephanie
Meuwissen, Hilaire
Ferdman, Ronald M.
Wallace, Mark
Desai, Mukesh M.
Taur, Prasad
Badolato, Raffaele
Soltesz, Beata
Schnopp, Christina
Jansson, Annette F.
Ayvaz, Deniz
Shabashova, Nadejda
Chernyshova, Liudmyla
Bondarenko, Anastasia
Moshous, Despina
Neven, Benedicte
Boubidi, Chahinez
Ailal, Fatima
Giardino, Giuliana
Del Giacco, Stefano
Bougnoux, Marie-Elisabeth
Imai, Kohsuke
Okawa, Teppei
Mizoguchi, Yoko
Ozaki, Yusuke
Takeuchi, Masato
Hayakawa, Akira
Logering, Birgit
Reich, Kristian
Buhl, Timo
Eyerich, Kilian
Schaller, Martin
Arkwright, Peter D.
Gennery, Andrew R.
Cant, Andrew J.
Warris, Adilia
Henriet, Stefanie
Mekki, Najla
Barbouche, Ridha
Ben Mustapha, Imen
Bodemer, Christine
Polak, Michel
Grimprel, Emmanuel
Burgel, Pierre-Regis
Fischer, Alain
Hermine, Olivier
Debre, Marianne
Kocacyk, Dilara
Dhalla, Fatima
Patel, Smita Y.
Moens, Leen
Haerynck, Filomeen
Dullaers, Melissa
Hoste, Levi
Sanal, Ozden
Kilic, Sara Sebnem
Roesler, Joachim
Lanternier, Fanny
Lortholary, Olivier
Fieschi, Claire
Church, Joseph A.
Roifman, Chaim
Yuenyongviwat, Araya
Peterson, Part
Boisson-Dupuis, Stephanie
Abel, Laurent
Marciano, Beatriz E.
Netea, Mihai G.
Korganow, Anne-Sophie
Paillard, Catherine
Boutboul, David
Toubiana, Julie
Okada, Satoshi
Hiller, Julia
Oleastro, Matias
Lagos Gomez, Macarena
Aldave Becerra, Juan Carlos
Ouachee-Chardin, Marie
Fouyssac, Fanny
Girisha, Katta Mohan
Etzioni, Amos
Van Montfrans, Joris
Kerns, Leigh Ann
Belohradsky, Bernd
Blanche, Stephane
Bousfiha, Aziz
Rodriguez-Gallego, Carlos
Meyts, Isabelle
Metadata
Show full item recordAbstract
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-Guerin 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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