Does CVID exist in children? A genetic architecture and manifestation map derived from 7,525 patients.

Diagnosing common variable immunodeficiency (CVID) in childhood remains contentious, as monogenic inborn errors of immunity (IEIs) are increasingly recognized in CVID-like phenotypes. We analyzed 7,525 ESID Registry patients with a clinical diagnosis of CVID to investigate age-dependent genetic architecture and associated phenotypes. Among living CVID patients, monogenic defects were identified in 82 of 251 children younger than 18 years (32.7%) versus 447 of 5,225 adults (8.6%; OR: 5.18, 95% CI: 3.86-6.92). Pediatric-onset disease (<18 years) likewise demonstrated increased monogenic underpinnings (OR: 1.88, 95% CI: 1.56-2.27), strongest with onset before 4 years (OR: 2.99, 95% CI: 2.38-3.78). Monogenic "CVID" was more likely associated with immune dysregulation at presentation (OR: 1.98, 95% CI: 1.66-2.36) and negatively linked to infection-predominant manifestations (OR: 0.67, 95% CI: 0.56-0.81). Physician-entered "additional-gene" annotations suggested multigene constellations in 1.6% of patients and identified recurrently recorded variants in other IEI-associated genes, including TCF3, PIK3CD, and KMT2D, among unresolved cases. These findings support "pediatric CVID" as a provisional label requiring systematic genetic evaluation.