D2.388 - Is Sarcoidosis a preliminary feature of Inborn Errors of Immunity?

Background: Sarcoidosis is a granulomatous inflammatory disorder with an uncertain etiology that has been traditionally classified as an immune-mediated disease. Increasing evidence suggests that sarcoidosis-like granulomatous inflammation may represent a manifestation of an underlying inborn error of immunity (IEI), rather than primary autoimmunity. GIMAP5 deficiency is characterized by impaired T-cell survival and defective antiviral immune control.  

Aim: We present the clinical, immunological, and genetic findings of two siblings from a consanguineous family who were initially diagnosed with sarcoidosis.

Results: The first patient presented in childhood with bilateral uveitis and biopsy-proven non-caseating granulomas and subsequently developed recurrent hemophagocytic lymphohistiocytosis, progressive Epstein–Barr virus (EBV) reactivation, and EBV-associated lymphoproliferative disease. The second patient exhibited lymphoproliferation, hypogammaglobulinemia, cytopenias, progressive renal and hepatic involvement, and clinical features raising suspicion of sarcoidosis, reflecting variable expressivity of the same genetic defect. Following the identification of a homozygous missense variant in GIMAP5 (c.667C>T; p.L223F) in his sister by whole-exome sequencing, targeted Sanger sequencing was performed and confirmed the same homozygous variant.

Conclusion: In this context, sarcoidosis may be considered a clinical phenotype of primary immunodeficiency, in which the conditions for granuloma formation are established by chronic immune dysregulation and impaired viral control. This perspective raises an important question: Could sarcoidosis represent a preliminary or early clinical manifestation of inborn errors of immunity (IEI)? We suggest that the formation of granulomas in affected individuals may be influenced by persistent viral antigen exposure in the setting of defective immune surveillance. These cases broaden the clinical spectrum of GIMAP5 deficiency and underscore the importance of considering monogenic immune disorders in patients with early-onset, atypical, or treatment-refractory sarcoidosis-like disease.