Background/Purpose: Immune dysregulation, including autoimmunity, is one of the known clinical manifestations of inborn errors of immunity (IEI). We aim to evaluate IEI discovered by targeted genetic testing in pediatric patients presenting with immune dysregulation and rheumatologic diagnosis.

Methods: We retrospectively reviewed charts of 348 patients aged ≤ 18 years with suspected IEI who had clinical targeted gene panel testing (Invitae^®) for IEI sent at a tertiary pediatric hospital in the U.S. over a 5-year study period, March 2018 – March 2023. We identified patients with the genetic testing sent primarily due to immune dysregulation (autoimmunity, fevers, atopy, lymphoproliferation, and malignancy). We reviewed their clinical and laboratory data and genetic testing results. The study is reviewed and approved by our institution review board (IRB).

Results: Of 348 patients, 222 (64%) had targeted gene panels for IEI sent during the study period for immune dysregulation with or without infections. Of these 222 patients, the median age was 6.3 years (IQR 2.1 -11.7 years), 51% were male, 86% Caucasian, and 10% African Americans. The primary indications of sending genetic testing for IEI in 222 patients include autoimmunity without lymphoproliferation (48%), fevers (35%), atopy (7%), hemophagocytic lymphohistiocytosis (3%), autoimmunity with lymphoproliferation (3%), EBV susceptibility and lymphoproliferation (3%), and malignancy (< 1%). In a subset of 40 patients who had rheumatologic diagnoses before genetic testing, we found IEI in 5 patients (12.5%) and these include pathogenic or likely pathogenic variants in CTLA4 (n=1), IKZF1 (n=1), NLRC4 (n=1), and TNFAIP3 (n=2) genes. The IEI diagnoses led to changes in treatment in all patients. Our limitations include a potential selection bias as most of these patients had the genetic testing done due to multiple autoimmunity, or rheumatologic diagnoses with refractory and/or atypical manifestations so the results may not apply to all rheumatology patients we encounter in clinical practice.  In addition, the field is moving toward whole exome/genome sequencing that may capture more patients with IEIs than targeted gene panels, therefore our results could potentially be underestimated.

Conclusion: Approximately 1 in 8 pediatric patients with rheumatologic diagnoses and clinically suspected immune dysregulation seen in Immunology and/or Rheumatology clinic had IEI in our cohort.

« Back to ACR Convergence 2024

ACR Meeting Abstracts - https://acrabstracts.org/abstract/uncovering-inborn-errors-of-immunity-in-pediatric-rheumatology/