Chronic Granulomatous Disease: A Case Series of Intrafamilial Phenotypic Variability with a New CYBB Variant

Chronic granulomatous disease (CGD) is an inborn error of immunity that causes impaired phagocyte function, generating an inflammatory phenotype and recurrent fungal and bacterial infections. Although there is a classic CGD phenotype, a variability of symptoms is observed between cases. In this study, we report the case of a family with 8 children diagnosed with CGD who, despite sharing the same variant, present heterogeneous symptoms and severity. P1 (index case) presented at two months of age with severe gastrointestinal infection requiring intensive care unit admission, followed by bronchiolitis and late-onset BCGitis. Immunological investigation revealed an abnormal dihydrorhodamine test and a CYBB mutation (c.T769A:p.C257S). This missense variant has not been previously reported in population databases such as gnomAD, ClinVar, or dbSNP. Family screening of 22 relatives identified 5 female carriers and 7 additional affected boys. Clinical features among the other CGD patients ranged from recurrent respiratory and gastrointestinal infections (P2, P3), to Behçet-like symptoms (P4, P5), and atypical manifestations including allergic features, blepharitis, and skin desquamation (P6–P8). Notably, some cases were initially misdiagnosed or under-recognized due to milder or nonspecific symptoms. With this study, we can learn more about CGD's phenotypic heterogeneity, emphasizing the importance of family genetic screening, even in less severe cases. What is crucial is to reduce diagnostic delay and prevent complications. Our findings reaffirm the need for attention among clinicians of the potential phenotypic diversity of CGD, even within the same family.