Somatic mosaicism of CYBB causing atypical CGD with inflammatory symptoms

Chronic granulomatous disease (CGD) is a rare inborn error of immunity (IEI) characterized by a defective respiratory burst in phagocytes and defective clearance of phagocytosed microorganisms. CGD is caused by a defect of the enzyme NADPH oxidase, resulting in severe and life-threatening infections in affected children. The genetically heterogeneous X-linked recessive form of CGD (XL-CGD) is caused by mutations in the CYBB gene. XL-CGD is typically diagnosed early in life, usually before the age of 3 years. The present report describes a boy aged 9 years and 11 months who presented with oral ulcers, cutaneous lesions, and uveitis. Whole-exome sequencing (WES) detected a mosaic, pathogenic nonsense variant (p.Arg157X) in CYBB. This pathogenic variant was present in ~ 60% of peripheral leukocytes in this patient, a percentage sufficient to result in defective production of reactive oxygen species (ROS), but not life-threatening infections, including BCG lymphadenitis following BCG vaccination. This study describes a somatic mosaicism mutation in the CYBB gene that can cause atypical CGD with inflammatory symptoms.