ClinVar

In a boy with destructive midline granulomatous disease of the head and neck (CCHIDG; 233650), De Ravin et al. (2010) identified compound heterozygosity for 2 mutations in the RAG1 gene: a 1566G-T transversion, resulting in a trp522-to-cys (W522C) substitution, and a 1-bp deletion (1621delC; 179615.0025), resulting in a frameshift and premature termination after 30 novel residues. Each unaffected parent was heterozygous for 1 of the mutations. The patient had a complicated medical history. He had a history of myasthenia gravis with thymectomy at age 10 years, and a history of recurrent ear and sinus infections. The thymus showed dysplastic features and absence of autoimmune regulator, indicating a defect in thymocyte maturation. Laboratory studies showed a decrease of IgG subclasses 2 and 4 and mild CD8+ T cell lymphopenia, whereas CD3+ T cells, CD19+ B cells, and NK cells were normal. He was treated for Wegener granulomatosis with chemotherapeutic agents, but developed severe lymphopenia and continued to have relapses of noninfectious granulomas. In vitro studies showed dysregulated cellular inflammatory responses to various stimuli, including increased production of IL1B (147720) and IL8 (146930). Functional studies showed that the W522C mutant had about 50% residual RAG1 activity, but the deletion mutation had no activity. An older sister had autoimmune cytopenias and antinuclear antibody-positive collagen vascular disease, with death at age 5 years. De Ravin et al. (2010) concluded that the proband had a phenotypic variant of RAG1 deficiency, with some residual enzyme activity being responsible for the later presentation and milder phenotype. The authors suggested a dysregulation of the inflammatory response to environmental antigens in this patient.