Combined Immunodeficiency With Late-Onset Progressive Hypogammaglobulinemia and Normal B Cell Count in a Patient With RAG2 Deficiency

Abstract

Proteins expressed by recombination activating genes 1 and 2 (RAG1/2) are essential in the process of V(D)J recombination that leads to generation of the T and B cell repertoires. Clinical and immunological phenotypes of patients with RAG deficiencies correlate well to the degree of impaired RAG activity and this has been expanding to variants of combined immunodeficiency (CID) or even milder antibody deficiency syndromes. Pathogenic variants that severely impair recombinase activity of RAG1/2 determine a severe combined immunodeficiency (SCID) phenotype, whereas hypomorphic variants result in leaky (partial) SCID and other immunodeficiencies. We report a patient with novel pathogenic compound heterozygous RAG2 variants that result in a CID phenotype with two distinctive characteristics: late-onset progressive hypogammaglobulinemia and highly elevated B cell count. In addition, the patient had early onset of infections, T cell lymphopenia and expansion of lymphocytes after exposure to herpes family viruses. This case highlights the importance of considering pathogenic RAG variants among patients with preserved B cell count and CID phenotype.

Consensus of the Italian Primary Immunodeficiency Network on transition management from pediatric to adult care in patients affected with childhood-onset inborn errors of immunity

“…61 In such cases a potential progressive immunologic deterioration may be expected. [62][63][64] The specificity and critical issues of transition of care of patients with this condition are summarized in Table II.…”

Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells

“…All patients displayed profound lymphopenia as compared to aged-matched healthy ranges 24 (Extended Data Fig. 1c–f ), except P13 who had chronic Epstein–Barr virus (EBV) and Cytomegalovirus (CMV) viremia with lymphoproliferation 25 . Asymptomatic P1 was considered to be antigen-naive (pRD-N), whereas symptomatic P2–16 were grouped as antigen-experienced patients (pRD-Ag).…”

SCID newborn screening: What we’ve learned

“…Individuals with the most mild ADA, IL-2 receptor (gamma), recombination activating gene (RAG)1, and RAG2 mutations may not present until adulthood, and presumably may have sufficient TRECs at birth to escape identification by NBS. [25][26][27] The 94% survival rate of California NBS SCID following treatment is outstanding compared with historical controls or to populations without newborn screening, 7 but the 3 deaths in Table II remind us that challenges remain. In 2 fatalities, infection with cytomegalovirus (CMV) was involved, most likely acquired postnatally from intermittent virus shed in breast milk of mothers who had experienced remote CMV infection.…”