Idiopathic CD4 T lymphopenia without autoimmunity or granulomatous disease

A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4 T lymphocytopenia (ICL). Her clinical con-dition remained stable over the past 10 years without infections, any granulo-matous disease, or autoimmunity. Immu-nophenotyping demonstrated strongly re-duced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-V repertoire was poly-clonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo prolifera-tion. Patient-derived CD34 hematopoi-etic stem cells could not repopulate RAG2/IL2Rc/ mice, indicating the lymphoid origin of the defect. We identi-fied 2 novel missense mutations in RAG1 (p.Arg474Cys and p.Leu506Phe) result-ing in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAG mutations from severe immune defects to an almost normal condition. (Blood. 2011; 117(22):5892-5896