Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of immune dysregulation caused by defects in the extrinsic apoptotic pathway. It is characterized by nonmalignant lymphoproliferation, autoimmune cytopenias, and expansion of αβ+ CD4- CD8- double-negative T cells (DNT). Current diagnostic criteria combine clinical features with laboratory markers such as DNT, vitamin B12, and soluble FAS ligand (sFASL) [1].
An 8-year-old male was referred for persistent splenomegaly, multiple lymphadenopathies since infancy, and recurrent idiopathic thrombocytopenic purpura treated at age 5 with corticosteroids and intravenous immunoglobulin. Infectious, oncohematologic, and storage diseases were ruled out.
IgG: 1,214 mg/dL; IgA: 168 mg/dL; IgM: 84 mg/dL; serum protein electrophoresis: polyclonal hypergammaglobulinemia; IgG subclasses, anti-pneumococcal, and tetanus toxoid antibodies: within normal limits; vitamin B12: 1,687 pg/mL; sFASL: >1,000 pg/mL; DNT: 8.5% (128 cells/μL); next-generation sequencing panel of 513 genes for inborn errors of immunity (including FAS, FASLG, CASP10, CASP8, NRAS, PRKCD, CTLA4, LRBA): no pathogenic or likely pathogenic variants detected. Reopening of the genetic panel in process: NKT is yet to be performed; functional apoptosis assay is yet to be performed. The patient meets the two required criteria (lymphoproliferation and elevated DNT) and three of the secondary accessory criteria (autoimmune cytopenias, hypergammaglobulinemia, and elevated biomarkers), supporting a probable diagnosis of ALPS. Treatment with rapamycin and eltrombopag was initiated, with clinical stability achieved.
Robust clinical and immunophenotypic evidence enabled timely initiation of immunomodulatory therapy in this case, having probable diagnosis without genetic confirmation. This case highlights the critical role of mid-complexity laboratories in the identification of IEIs and underscores the need to expand access to molecular and/or functional testing to achieve definitive diagnoses and ensure diagnostic and therapeutic equity.
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