Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder caused by mutations in NADPH oxidase subunits, leading to an inability to produce reactive oxygen species, recurrent infections, and autoimmune phenomena. The most common form, X-linked CGD, predominantly affects males. We describe a de novo mutation in the CYBB gene with skewed X-inactivation (lyonization) resulting in a symptomatic CGD carrier female.
Presented at age 4 with fever and rash, diagnosed with incomplete Kawasaki disease, treated with IVIG. Later, the patient had a Burkholderia cepacia thigh abscess. Additionally, she had perianal streptococcal dermatitis, multiple ear infections, upper respiratory infections, intermittent oral ulcers, and pustular cutaneous infections.
Dihydrorhodamine (DHR) assay had only 17.7% activation, in line with a CGD phenotype. Genetic testing identified a likely pathogenic CYBB variant, c.45 + 2dup (intronic), heterozygous. Additional labs further showed absent expression of gp91phox. This was a de novo variant, not present in parents’ genetics and both with normal DHR and gp91phox expression. Subsequent three-month DHR trends showed 13.1% and 12.1% activation, respectively. The patient was recommended triple therapy (TMP-SMX, itraconazole, and IFN-gamma) prophylaxis; however, parents opted for TMP-SMX only. The patient has been well controlled on that therapy. Skin biopsy also showed cutaneous lupus, well controlled after starting daily hydroxychloroquine.
The lack of awareness of highly symptomatic CGD carriers can lead to significant delay in diagnosis and management of their CGD phenotype with recurrent infections and multiple autoimmunity phenomena.
