Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Toubiana;Julie, Okada;Satoshi, Hiller;Julia, Oleastro;Matias, Gomez;Macarena Lagos, Becerra;Juan Carlos Aldave, Ouachãe chardin;Marie, Fouyssac;Fanny, Girisha;Katta Mohan, Etzioni;Amos, Van Montfrans;Joris, Camcioglu;Yildiz, Kerns;Leigh Ann, Belohradsky;Bernd, Blanche;Stephane, Bousfiha;Aziz, Rodriguez gallego;Carlos, Meyts;Isabelle, Kisand;Kai, Reichenbach;Janine, Renner;Ellen D. , Rosenzweig;Sergio, Grimbacher;Bodo, Van De Veerdonk;Frank L. , 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;Caroline Thumerelle;Antoine Toulon;Jacinta Bustamante;Natalia Tahuil;Aicha Salhi;Sorina Boiu;Charu Chopra;Daniela Di Giovanni;Liliana Bezrodnik;JeannetteBoutros;Caroline Thomas;Gina Lacuesta;Sarah Jannier;Anne-Sophie Korganow;Catherine Paillard;David Boutboul;M´elanie Bu´e;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;MargaritaOrtega-Cisneros;Mariana Cortina;Mehrnaz Mesdaghi;MohammadNabavi;Teresa Español;Maia Teresa Martinez- Saavedra;Nima Rezaei;Samaneh Zoghi;Malgorzata Pac;Vincent Barlogis;Gabriel Revon-Rivire;Yishai Haimi-Cohen;Ronen Spiegel;Dan Miron;Jabir Bouchaib;Lizbeth Blancas-Galicia;Beata Toth;Barbara Drexel;Pierre Simon Roherlich;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 Logering;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 BenMustapha;Christine Bodemer;Michel Polak;EmmanuelGrimprel;Pierre-R´egis Burgel;Alain Fischer;Olivier Hermine;Marianne Debr´e;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;Part Peterson;Stéphanie Boisson-Dupuis;Laurent Abel;Beatriz E. Marciano;Mihai G. Netea

2016-01-01

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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.