Abstract
PURPOSE: To review the clinical and laboratory spectrum of RAG gene defects in humans, and discuss the mechanisms underlying phenotypic heterogeneity, the basis of immune dysregulation, and the current and perspective treatment modalities. METHODS: Literature review and analysis of medical records RESULTS: RAG gene defects in humans are associated with a surprisingly broad spectrum of clinical and immunological phenotypes. Correlation between in vitro recombination activity of the mutant RAG proteins and the clinical phenotype has been observed. Altered T and B cell development in this disease is associated with defects of immune tolerance. Hematopoietic cell transplantation is the treatment of choice for the most severe forms of the disease, but a high rate of graft failure has been observed. CONCLUSIONS: Phenotypic heterogeneity of RAG gene defects in humans may represent a diagnostic challenge. There is a need to improve treatment for severe, early-onset forms of the disease. Optimal treatment modalities for patients with delayed-onset disease presenting with autoimmunity and/or inflammation remain to be defined.