Refereed journal article or data article (A1)

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome




List of Authors: Leiding Jennifer W, Vogel Tiphanie P, Santarlas Valentine GJ, Mhaskar Rahul, Smith Madison R, Carisey Alexandre, Vargas-Hernández Alexander, Silva-Carmona Manuel, Heeg Maximilian, Rensing-Ehl Anne, Neven Bénédicte, Hadjadj Jérôme, Hambleton Sophie, Ronan Leahy Timothy, Meesilpavikai Kornvalee, Cunningham-Rundles Charlotte, Dutmer Cullen M, Sharapova Svetlana O, Taskinen Mervi, Chua Ignatius, Hague Rosie, Klemann Christian, Kostyuchenko Larysa, Morio Tomohiro, Thatayatikom Akaluck, Ozen Ahmet, Scherbina Anna, Bauer Cindy S, Flanagan Sarah E, Gambineri Eleonora, Giovannini-Chami Lisa, Heimall Jennifer, Sullivan Kathleen E, Allenspach Eric, Romberg Neil, Deane Sean G, Prince Benjamin T, Rose Melissa J, Bohnsack John, Mousallem Talal, Jesudas Rohit, Santos Vilela Maria Marluce Dos, O'Sullivan Michael, Pachlopnik Schmid Jana, Průhová Štěpánka, Klocperk Adam, Rees Matthew, Su Helen, Bahna Sami, Baris Safa, Bartnikas Lisa M, Chang Berger Amy, Briggs Tracy A, Brothers Shannon, Bundy Vanessa, Chan Alice Y, Chandrakasan Shanmuganathan, Christiansen Mette, Cole Theresa, Cook Matthew C, Desai Mukesh M, Fischer Ute, Fulcher David A, Gallo Silvanna, Gauthier Amelie, Gennery Andrew R, Gonçalo Marques José, Gottrand Frédéric, Grimbacher Bodo, Grunebaum Eyal, Haapaniemi Emma, Hämäläinen Sari, Heiskanen Kaarina, Heiskanen-Kosma Tarja, Hoffman Hal M, Gonzalez-Granado Luis Ignacio, Guerrerio Anthony L, Kainulainen Leena, Kumar Ashish, Lawrence Monica G, Levin Carina, Martelius Timi, Neth Olaf, Olbrich Peter, Palma Alejandro, Patel Niraj C, Pozos Tamara, Preece Kahn, Lugo Reyes Saúl Oswaldo, Russell Mark A, Schejter Yael, Seroogy Christine, Sinclair Jan, Skevofilax Effie, Suan Daniel, Suegeorgz Daniel, Szabolcs Paul, Velasco Helena, Warnatz Klaus, Walkovich Kelly, Worth Austen; STAT3 GOF Working Group members, Seppänen Mikko RJ, Torgerson Troy R, Sogkas Georgios, Ehl Stephan, Tangye Stuart G, Cooper Megan A, Milner Joshua D, Forbes Satter Lisa R

Publisher: Elsevier

Publication year: 2022

Journal: Journal of Allergy and Clinical Immunology

Journal name in source: The Journal of allergy and clinical immunology

Journal acronym: J Allergy Clin Immunol

ISSN: 0091-6749

eISSN: 1097-6825

DOI: http://dx.doi.org/10.1016/j.jaci.2022.09.002

URL: https://doi.org/10.1016/j.jaci.2022.09.002


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.


Last updated on 2022-09-12 at 09:56