The recognition of disorders of immune dysregulation, particularly those presenting with lymphoproliferation and systemic autoimmunity (International Union of Immunological Societies [IUIS] Group 4.6), has markedly increased in recent years. Initially, many of these conditions were collectively classified as Autoimmune Lymphoproliferative Syndrome (ALPS); however, the advent and dissemination of next-generation sequencing enabled the identification of patients with distinct genetic etiologies despite sharing overlapping clinical and immunological features. Through a national collaborative effort, the Centro nacional de Erros Inatos da Imunidade e Imunodesregulação (CNE3i) has systematically collected data on ALPS and ALPS-related disorders across Brazil since 2024. Here, we report the first year of CNE3i’s dataset on ALPS and ALPS-like diseases, highlighting their genetic diversity, clinical presentations, and immunological signatures within the Brazilian population. A total of 33 individuals were identified, 33.3% female (n = 11), from all 5 major regions of Brazil, with a mean age of 17 years (range 6–56 years) and a mean diagnostic delay of 5 years. Lymphadenopathy was the most common clinical finding (94%, n =31), followed by diffuse splenomegaly (72.7%, n = 24), hepatomegaly (54.6%, n = 18), and cytopenia (48.5%, n = 16), all present in a substantial proportion of patients. An elevated double-negative T cell (DNTs) was found in 14 individuals (42%), and diverse monogenic etiologies were identified (n = 15) (supplemental table). Despite extensive investigation, around 50% of the time, a causative gene could not be found. Most patients received corticosteroids as first-line therapy, followed by an mTOR inhibitor (41%) and mycophenolate mofetil (44%). The CNE3i Brazilian ALPS cohort reflects the complex phenotypic overlap between ALPS and ALPS-like disorders, underscoring the central role of autoimmune cytopenias and lymphoproliferation.
The identification of canonical FAS mutations and ALPS-like defects (e.g., LRBA, TNFAIP3, and CTLA4) reinforces the importance of broad genetic screening in cases of immune dysregulation. These findings contribute to a more refined understanding of the genetic and clinical heterogeneity of IEIs and support optimized therapeutic strategies, particularly involving mTOR inhibition and a selective PI3Kδ inhibitor.
FINEP funding: 0956/24; FAPESP funding: 2023/09965-0; Instituto de Investigação em Imunologia funding CNPQ/MCTI: 408685/2024-7
