e-Article
Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.
Document Type
article
Author
Rensing-Ehl, Anne; Neven, Bénédicte; Hadjadj, Jérôme; Hambleton, Sophie; Ronan Leahy, Timothy; Meesilpavikai, Kornvalee; Cunningham-Rundles, Charlotte; Dutmer, Cullen; Sharapova, Svetlana; Taskinen, Mervi; Chua, Ignatius; Hague, Rosie; Klemann, Christian; Kostyuchenko, Larysa; Morio, Tomohiro; Thatayatikom, Akaluck; Ozen, Ahmet; Scherbina, Anna; Bauer, Cindy; Flanagan, Sarah; Gambineri, Eleonora; Giovannini-Chami, Lisa; Heimall, Jennifer; Sullivan, Kathleen; Allenspach, Eric; Romberg, Neil; Deane, Sean; Prince, Benjamin; Rose, Melissa; Bohnsack, John; Mousallem, Talal; Jesudas, Rohith; Santos Vilela, Maria; OSullivan, Michael; Pachlopnik Schmid, Jana; Průhová, Štěpánka; Klocperk, Adam; Rees, Matthew; Su, Helen; Bahna, Sami; Baris, Safa; Bartnikas, Lisa; Chang Berger, Amy; Briggs, Tracy; Brothers, Shannon; Bundy, Vanessa; Grunebaum, Eyal; Haapaniemi, Emma; Hämäläinen, Sari; Heiskanen, Kaarina; Heiskanen-Kosma, Tarja; Hoffman, Hal; Gonzalez-Granado, Luis; Guerrerio, Anthony; Kainulainen, Leena; Kumar, Ashish; Lawrence, Monica; Levin, Carina; Martelius, Timi; Neth, Olaf; Olbrich, Peter; Palma, Alejandro; Patel, Niraj; Pozos, Tamara; Preece, Kahn; Lugo Reyes, Saúl; Russell, Mark; Schejter, Yael; Seroogy, Christine; Sinclair, Jan; Skevofilax, Effie; Suan, Daniel; Suez, Daniel; Szabolcs, Paul; Velasco, Helena; Warnatz, Klaus; Walkovich, Kelly; Worth, Austen; Seppänen, Mikko; Torgerson, Troy; Sogkas, Georgios; Ehl, Stephan; Tangye, Stuart; Cooper, Megan; Milner, Joshua; Forbes Satter, Lisa; Leiding, Jennifer; Vogel, Tiphanie; Santarlas, Valentine; Mhaskar, Rahul; Smith, Madison; Carisey, Alexandre; Vargas-Hernández, Alexander; Silva-Carmona, Manuel; Chandrakasan, Shanmuganathan; Christiansen, Mette; Cole, Theresa; Cook, Matthew; Desai, Mukesh; Fischer, Ute
Source
Journal of Allergy and Clinical Immunology. 151(4)
Subject
Language
Abstract
BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.