ALPS-like Disorder Linked with STAT3 Mutation: De Novo Variant with Bicytopenia and Literature Review

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Introduction/Objective: Autoimmune lymphoproliferative syndrome-like (ALPS-like) disorders are inherited conditions caused by non-FAS pathway mutations that clinically mimic ALPS, presenting with lymphoproliferation, autoimmunity, and cytopenias. This study describes a patient with STAT3-related ALPS-like disease that was initially misdiagnosed as ALPS and compares his clinical, immunological, and molecular features with those of previously reported cases to highlight diagnostic distinctions from classical ALPS. Methods: Clinical data were obtained from direct examination and medical records. Whole-Exome Sequencing (WES) identified the causative mutation. A literature review using PubMed, Web of Science, and Scopus retrieved previously reported ALPS-like cases with STAT3 mutations for comparative analysis of clinical, immunological, and molecular findings. results: We report a 10-year-old boy with bicytopenia (thrombocytopenia and neutropenia), autoimmune thrombocytopenic purpura, refractory lymphadenopathy, splenomegaly, and recurrent infections, initially misdiagnosed as ALPS. Elevated double-negative T cells and vitamin B12 levels were detected. WES revealed a heterozygous de novo STAT3 mutation (p.L666V). The patient responded well to JAK inhibitor therapy. Review of reported STAT3-mutant ALPS-like cases (66 cases) showed immune thrombocytopenia as the most common cytopenia, often combined with autoimmune hemolytic anemia, variable hypogammaglobulinemia, reduced Treg cells, and increased double-negative T cells. Results: We report a 10-year-old boy with bicytopenia (thrombocytopenia and neutropenia), autoimmune thrombocytopenic purpura, refractory lymphadenopathy, splenomegaly, and recurrent infections, initially misdiagnosed as ALPS. Elevated double-negative T cells and vitamin B12 levels were detected. WES revealed a heterozygous de novo STAT3 mutation (p.L666V). A reduced frequency of Treg cells was observed in our case. The patient responded well to JAK inhibitor therapy. Review of reported STAT3-mutant ALPS-like cases (66 cases) showed that immune thrombocytopenia was the most common cytopenia, often accompanied by autoimmune hemolytic anemia, variable hypogammaglobulinemia, reduced Treg cells, and increased double-negative T cells. Discussion: STAT3 gain-of-function–associated ALPS-like disease can closely mimic classical ALPS due to overlapping clinical and immunological features, including elevated double-negative T cells, which may lead to diagnostic challenges. Conclusion: This case highlights that STAT3 GOF ALPS-like disease can closely mimic classical ALPS, and that integrating genetic analysis with immunological assessment is essential for accurate diagnosis and guiding targeted therapy

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