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

INTRODUCTION

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). 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.