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Published January 1, 2023 | Version v1
Journal article Open

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

Creators

  • 1. Lake Erie Coll Osteopath Med, Erie, PA USA
  • 2. Univ S Florida, Dept Internal Med, Morsani Coll Med, Tampa, FL USA
  • 3. St Jude Childrens Res Hosp, Dept Cell & Mol Biol, Memphis, TN USA
  • 4. Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX USA
  • 5. Univ Freiburg, Med Ctr, Fac Med, Inst Immunodeficiency,Ctr Chron Immunodeficiency, Freiburg, Germany
  • 6. Inst Imagine, INSERM, UMR 1163, Lab Immunogenet Pediat Autoimmune Dis, Paris, France
  • 7. Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
  • 8. Childrens Hlth Ireland Crumlin, Dublin, Ireland
  • 9. Mt Sinai Sch Med, Dept Med, New York, NY USA
  • 10. Univ Colorado, Sch Med, Childrens Hosp Colorado, Aurora, CO USA
  • 11. Belarusian Res Ctr Pediat Oncol Hematol & Immunol, Minsk, BELARUS

Description

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. (J Allergy Clin Immunol 2023;151:1081-95.)

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