Baba et al. demonstrate the utility of multidisciplinary genetic evaluation for identifying inborn errors of immunity in adult rheumatology practice. They establish a workflow that improves diagnostic precision and management for patients with atypical rheumatic and musculoskeletal diseases.

A subset of patients evaluated for immune dysregulation presents with increased proportions of TCR γδ cells despite normal total lymphocyte counts. Corresponding to this phenotype, the authors report a case of a somatic TCR γδ–specific STAT5B mutation that is molecularly amenable to tailored immune modulation. This raises awareness of druggable TCR γδ–intrinsic, genetically determined immune dysregulation.

The authors identify three novel mutations in AIRE and detect T cell defects in patients with APS-1. Furthermore, they review the literature and identify additional clinical features, and define mutational hotspots suitable for targeted sequencing. These parameters could facilitate the timely identification of APS-1, which impacts the early initiation of treatment.

We report the first detailed immunological characterization of a DEGCAGS patient, showing that biallelic ZNF699 loss-of-function variants can cause syndromic combined immunodeficiency and that DNA methylation profiling improves diagnostic precision in selected inborn errors of immunity.

Allogeneic HCT substantially addresses immunodeficiency, immune dysregulation, and Epstein-Barr virus–positive smooth muscle tumors in patients with CARMIL2 deficiency and should be offered shortly following diagnosis.

We report a deep intronic FOXP3 pathogenic variant that was investigated by RNA sequencing in heterozygous female carriers.

Hematopoietic stem cell transplantation is a curative option for children with MSMD. Outcomes improve when conditioning is tailored to genetic defects: Flu/Treo for IL-12 deficiency and Flu/Treo/TT with pretransplant immunosuppression for IFN-γ defects. Multidisciplinary infection management and long-term follow-up are essential to optimize survival and quality of life.