STAT3 gain-of-function mutation in an adult patient

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Germline gain-of-function (GOF) mutations in the STAT3 gene are associated with lymphoproliferation, autoimmunity, and immunodeficiency.
• Common Variable Immunodeficiency (CVID) is a heterogeneous disorder often characterized by hypogammaglobulinemia and recurrent infections.
• STAT3 GOF mutations can present with overlapping features of CVID, autoimmune lymphoproliferative syndrome (ALPS), and other immune dysregulation syndromes.

Purpose of the Study:

• To report a case of STAT3 gain-of-function mutation presenting in adulthood with features initially diagnosed as CVID.
• To highlight the importance of genetic testing in CVID patients with significant lymphoproliferation and autoimmunity.
• To emphasize the potential benefit of targeted therapies for STAT3 GOF mutations.

Main Methods:

• Whole exome sequencing was used to identify the STAT3 mutation.
• Sanger sequencing was employed for mutation validation.
• Clinical data review and retrospective analysis of patient history were performed.

Main Results:

• A heterozygous STAT3 gain-of-function mutation (c.2141C>T, p.P714L) was identified in an adult patient.
• The patient presented with recurrent infections, autoimmune hemolytic anemia, hepatosplenomegaly, lymphadenopathy, and lymphocytic interstitial pneumonia.
• The patient died due to severe pulmonary disease, with limited access to targeted therapies.

Conclusions:

• STAT3 GOF mutations should be suspected in patients with early-onset lymphoproliferative disease, autoimmunity, and hypogammaglobulinemia, particularly within the CVID cohort.
• Timely genetic diagnosis can enable the implementation of targeted treatments, such as JAK inhibitors and IL-6 receptor antagonists.
• Targeted therapies hold the potential to alter the disease course and improve outcomes in patients with STAT3 GOF mutations.