Chronic aseptic osteomyelitis, cavitated lung disease, and eosinophilia as manifestations of a heterozygous pathogenic variant of RAG1. Case report.

RAG1 and RAG2 genes encode proteins that initiate VDJ recombination to generate specific LT and LB receptors. Mutations in these genes are related to the appearance of autoreactive cells involved in the genesis of immunodeficiencies and autoimmunity.

14-yo male with history of left knee pain and edema with walking impairment for 3 months. Firstly approached due to subacute osteomyelitis and soft tissue abscess in the left femur, with no infectious agent isolated. The laboratory studies showed serum hypereosinophilia, hypergammaglobulinemia and isolated lymphopenia with normal T cells, accompanied by a disseminated multi-cystic pattern bilateral cavitated lung disease, with no identified microorganism. A genetic sequencing panel was performed, reporting a heterozygous pathogenic variant in RAG1 (c.2065G>T (p.Glu689*) and uncertain significance variants in the CTC, HPS3, MALT1, MKL1, STAT5B genes. Human intravenous immunoglobulin was added (1 gr/kg) on a monthly basis with clinical improvement.

RAG1 defects can lead to T and B-cell autoreactivity. The RAG1 homozygous mutations are associated with a broad clinical phenotype (severe combined immunodeficiency, Omenn syndrome, autoimmunity with granulomas), depending on the protein residual function. Isolated T lymphopenia with clinical manifestations in patients with heterozygous mutations has been described. Our patient presents one of the phenotypes similar to those described in RAG1 defects, so this variant could play an important role. To confirm this suspicion, it is necessary to carry out functional studies, evaluate protein expression, and extend the genetic study to the family.

While there is the possibility of additional genetic defects not found in this case, the compatible phenotype enlights the need to study the effect of heterozygous and hypomorphic variants on RAG1. Since functional studies are not always available in our environment, clinical decisions for treatment continue to be the cornerstone for the improvement of these patients.

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