Case Report of an Infant Female with X-Linked Chronic Granulomatous Disease Due to a De Novo Mutation in CYBB and Extremely Skewed X-Chromosome Inactivation (Lyonization)

Rationale: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in any of the subunits of the NADPH oxidase all of which lead to an inability to generate reactive oxygen species, susceptibility to a narrow spectrum of organisms, and development of granuloma in those affected. X-linked CGD (CYBB) is the most common, occurring almost exclusively in boys. We describe a unique case of an infant female with X-linked CGD due to a de novo mutation in CYBB and extremely skewed X-chromosome inactivation (Lyonization).

Methods: Retrospective chart review was performed.

Results: Patient presented at 1 month age with Camplyobacter gastroenteritis and Serratia marcesens heel abscess. At 3 months she developed bilateral cervical adenitis and retropharyngeal abscess secondary to Klebsiella oxytoca. Dihydrorhodamine assay was consistent with X-linked CGD and evaluation of CYBB revealed a heterozygous mutation in exon 5 (c.469C>T), which leads to premature truncation of the protein. Karyotype confirmed XX genotype and further analysis showed extremely skewed Lyonization (<1% superoxide producing granulocytes). Her father is unaffected and her mother’s evaluation was not consistent with carrier status suggesting a de novo mutation. Prophylaxis with TMP-SMX, itranconazole, and IFNϒ ensued. The patient has been infection free for 6 months and under evaluation for hematopoietic stem cell transplant.

Conclusions: While there have been other reported cases of X-linked CGD in females, these cases still remain rare. A high index of suspicion is necessary for diagnosing CGD, especially in females. Determining the correct molecular defect can be difficult but provides valuable prognostic information.