Challenges in Diagnosis and Management of Adult Inborn Errors of Immunity: The Serbian Experience

Inborn errors of immunity (IEI) comprise a broad spectrum of disorders caused by genetic defects impairing innate and adaptive immunity, non-hematopoietic cell–mediated responses, and immune regulation. The Clinic of Allergy and Immunology at the University Clinical Center of Serbia serves as a national reference center for rare diseases and is the largest facility in the country managing patients with IEI. Since 2012, approximately 200 IEI patients have been followed at our center, the majority diagnosed with common variable immunodeficiency (CVID) and hereditary angioedema (HAE).

Within the highly heterogeneous CVID cohort, the most prominent noninfectious phenotypes included gastrointestinal involvement (28/57, 49.1%), granulomatous-lymphocytic interstitial lung disease (GLILD; 9/57, 15.7%), and malignancies (13/57, 22.8%). Our center has made significant contributions to the field by describing unique cases, including some with novel genetic variants or phenotypes, for the first time in the literature: a neurocognitive disorder in a patient with agammaglobulinemia caused by a SPI1 mutation; multiphasic acute disseminated encephalomyelitis in a patient with juvenile systemic lupus erythematosus and a C4A mutation; early-onset respiratory insufficiency in a 31-year-old monogenic CVID patient with an underlying PIK3CG mutation; and a CVID-like disorder with syndromic features and cognitive impairment in a patient harboring deletion of 23 genes affecting IRF2BP2. One of the most challenging cases involved rapidly progressive myelodysplastic syndrome in a 36-year-old female with somatic TP53 and SF3B1 mutations, initially presenting with Behçet-like features, successfully treated with hematopoietic stem cell transplantation.

Our experience illustrates not only the broad spectrum of IEI phenotypes managed at a national referral center but also emphasizes the pivotal role of specialized centers in identifying and characterizing ultra-rare cases. These observations advance the understanding of disease pathogenesis, facilitate early recognition of severe and atypical presentations, and provide a foundation for future research into novel genetic defects and their clinical implications.