Improving Diagnosis of Autoimmune Lymphoproliferative Immunodeficiency by Phenotype and Genotype Characterization

Inborn errors of immunodeficiency (IEI) that present with benign lymphoproliferation and immune cytopenia vary in severity and can be difficult to diagnose and treat. IEIs that present with mutations in the Fas signaling pathway are known as autoimmune lymphoproliferative syndrome (ALPS), which has a benign clinical course, and those without such mutations are known as ALPS-like diseases, which can be fatal and require curative therapy with hematopoietic stem cell transplant. These researchers suggested a new umbrella term — autoimmune lymphoproliferative immunodeficiency (ALPID) phenotype — for the spectrum of these conditions.

In a prospective, observational study, the researchers evaluated clinical, immunological, and genetic features for 431 children with suspected ALPID referred to a German IEI center from 2008 to 2022. Eligible patients had lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an IEI; bilineage autoimmune cytopenia; or autoimmune cytopenia and at least one additional sign of an IEI. Testing included biomarker studies (serum vitamin B12, soluble Fas ligand [sFasL]), targeted Sanger sequencing for ALPS-associated genes, and, if negative, whole exome and whole genome sequencing. Variants of unknown significance were considered causative or noncausative based on expert geneticist opinion.

Among 240 patients with sufficient genetic analyses, 71were diagnosed with ALPS; 54 with autosomal-dominant ALPID (AD-ALPID), mostly JAK-STAT signaling pathway disorders; 19 with other rare IEIs, and 17 with non-IEIs; 79 had unresolved diagnoses (ALPID-U). There were clinical distinctions among diagnoses: lymphadenopathy was more common with ALPS and AD-ALPID than with ALPID-U, while cytopenias were more frequent with ALPID-U. The established cutoffs for sFasL (>560 pg/mL) and vitamin B12 (>1255 pg/mL) had high sensitivity and specificity for diagnosis of ALPS in this cohort.