Combined immunodeficiencies in adulthood pose a diagnostic challenge. Mosaicism in genes classically associated with severe immunodeficiencies may underlie atypical phenotypes and complex clinical courses.
A 47-year-old male with a history of chronic Giardia lamblia diarrhea since age 2, recurrent respiratory infections, and suppurative otitis was diagnosed in childhood with primary immunodeficiency characterized by functional antibody deficiency. He received intravenous immunoglobulin (IVIG) until the year 2000. In 2009, he resumed IVIG due to severe pneumonia, bronchiectasis, and chronic sinusitis. He experienced persistent respiratory infections, severe chronic obstructive pulmonary disease, and prolonged hospitalizations. In 2022, he developed bilateral pneumonia post-COVID-19 with esophageal candidiasis and extended hypoxemia. Additional findings included recurrent warts, cutaneous sarcoid granuloma, and chronic skin ulcers. Immunologic workup revealed hypogammaglobulinemia with undetectable IgA, marked B cell lymphopenia, and persistent CD4/CD8 inversion (70%). Secondary causes were excluded. Given the progressive clinical course, a next-generation sequencing panel for inborn errors of immunity identified mosaic mutation for a likely pathogenic IL2RG variant (c.924G>, p.Ser308=), a gene classically associated with X-linked severe combined immunodeficiency (SCID-X1).
This case represents a milder form of X-linked combined immunodeficiency due to mosaicism in IL2RG. The presence of functional CD8+ T cells contributed to prolonged survival, albeit with ongoing infections and chronic pulmonary damage. The identification of mosaic variants in genes typically linked to severe phenotypes highlights the importance of advanced genetic testing in atypical presentations of primary immunodeficiency. This finding informs clinical follow-up, enables genetic counseling, and may guide personalized therapeutic approaches.
