Immunodeficiency Masqueraders

Classically described as an etiology of severe combined immunodeficiency (SCID), mutations in RAG1 and RAG2—encoding recombinase activating genes 1 and 2, respectively—have since been associated with a much wider clinical spectrum of disease, including Omenn syndrome, atypical SCID, and combined immunodeficiency with granulomas and/or autoimmunity.1 Unfortunately, lack of recognition of the clinical heterogeneity seen in RAG1/RAG2 deficiency has resulted in delayed diagnosis, suboptimal therapy, and even death for some affected individuals.2 A 2-year-old boy had recurrent candidiasis (oral/cutaneous), along with an accompanying history of recurrent otitis media and atopy (atopic dermatitis, food allergy, and asthma), for which he had received numerous courses of oral/topical antifungals, oral antibiotics, and oral/inhaled steroids, respectively. Immunophenotyping revealed essentially normal enumeration of T, B, and natural killer cells; mildly low serum IgG and IgM levels; normal serum IgA and IgE levels; and diminished lymphocyte proliferation to phytohemagglutinin. Mutations in CARD11—encoding caspase activation and recruitment domain 11—were first described as etiologies of SCID (biallelic, loss-of-function) and B-cell expansion with nuclear factor kappa B and T-cell anergy (monoallelic, gain-of-function), but the clinical spectrum of disease has since expanded to include varying degrees of immunodeficiency with or without severe atopy (monoallelic; dominant-negative).3-6Discussion Recent and ongoing advances in the understanding and characterization of primary immunodeficiency diseases have led to a crowded field of more than 350 monogenic defects, in which overlapping clinical phenotypes are common.7 Further still, differing mutations in a singular gene can result in significant clinical heterogeneity with distinct or even grossly disparate disease states. [...]a heightened clinical acumen, detailed immunophenotyping, and access to molecular diagnostics are paramount in the modern practice of clinical immunology.