Not all CGD cases present with the same severity. In particular, the autosomal recessive forms of the disease may have a milder more insidious clinical course [9
]. In contrast, patients with X-linked variants, which are due to mutations in the CYBB gene [1
], tend to present early in life with multiple, sometimes fatal, infections resulting from complete absence of NADPH oxidase function [6
]. To our knowledge, this is the first reported case in the literature of a patient with a CYBB gene mutation (c.252 G>A, p.Ala84Ala) presenting only isolated lung involvement. The phenotypic picture of this patient was remarkable because, despite having an X-linked mutation, he had residual neutrophil activation after stimulation, a pattern typically seen in autosomal recessive variants, where the ability of phagocytes to generate superoxide anion is only partially impaired [9
]. As a result, this child had an atypical mild form of X-linked CGD remaining undiagnosed for several years.
Prior reports have identified atypical presentations and adult forms of X-linked CGD resulting from rare CYBB mutations with residual NADPH oxidase. For instance, Brunner et al. reported an X-linked CGD case with partially preserved oxidase activity and sarcoidosis-like picture caused by an intraexonic splice defect in the gene encoding gp91-phox (CYBB exon 3, c.262G->A) [12
]. Another X-linked case with residual NADPH oxidase activity (in-frame triplet deletion in gp91-phox gene) was seen in an adult with multisystem disease that included staphylococcal lymphadenitis, recurrent pneumonia, and liver/renal abscesses [13
]. Similarly, a gp91-phox gene splice site mutation (5′intron3 GTAAG/GTAAA), with residual NADPH, was described in a 40-year-old man with liver abscesses (Staphylococcus aureus
) and septicemia (Salmonella enteritis
]. More severe phenotypes have also been reported in adults with point mutations in the CYBB gene's promoter (insertion of a T at position −54T to −56T), despite the presence of residual NADPH oxidase activity [15
]. Collectively, these clinical reports demonstrate that some CYBB mutations induce only partial loss of NAPDH function, which results in less severe phenotypes; however, this residual NAPDH oxidase activity is not sufficient to completely protect the patient against infections.
Independent of the severity, CGD is typically a condition characterized by multisystem compromise [1
]. Although pneumonia occurs in about 80% of CGD cases [16
], infections in other systems, such as skin, lymph nodes, or bones, are commonly present in this disease [1
]. In contrast, recurrent pneumonia was the only manifestation of CGD in our case. Because the differential diagnosis of such isolated lung involvement is broad, it is important to identify the pulmonary radiographic features suggestive of CGD that may allow timely diagnosis of this condition. In this regard, prior literature has described typical radiological patterns of granulomatous inflammation and infection in the lung of patients with CGD [17
], which include focal consolidation, abscess formation, reticulonodular opacities, and diffuse miliary infiltration [17
]. Lymphadenopathy, pulmonary fibrosis, pleural thickening, and contiguous extension of disease from the lungs to the pleura or chest wall (i.e., ribs or vertebral osteomyelitis) have also been reported in patients with CGD, particularly in those cases with infection by Aspergillus
]. Similarly, our patient had focal opacities with variable patterns, ranging from extensive diffuse nodularity (Figures and ) to large opacifications involving different segments and/or lobes of the lungs (Figures and ). There were essentially absence of hyperinflation and other signs of small airway disease in his chest radiographs and CT scan. Collectively, these radiographic images raised the concern for an underlying immunodeficiency, particularly a phagocytic defect like CGD, that could lead to isolated and recurrent lung abscesses and/or granulomas without significant compromise of the conductive airways.
Another clinical feature of importance when considering the diagnosis of CGD is the lack of response to standard antibiotic therapy during bacterial respiratory infections. This is because the underlying phagocytic defect results in vulnerability to uncommon microorganisms. Specifically, recurrent infections in patients with CGD are typically due to Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia,
]. Not surprisingly, our patient had a presumptive Aspergillus
lung infection, with positive titers in BAL fluid (Galactomannan testing) and a significant clinical response to antifungal therapy with voriconazole. However, Streptococcus viridans
, which is inherently a catalase negative bacteria, was isolated in BAL cultures (>100,000 colonies). In this regard, it is noteworthy that Streptococcus
species are a well-known cause of disease in neutropenic hosts [19
] and have recently been recognized as important pathogens in CGD [20
]. Indeed, streptococcal infections caused by S. intermedius
, S. mitis
, or S. anginosus
may lead to pyogenic liver abscesses in individuals with CGD [20
]. Moreover, S. viridans
have also been reported to cause mastoiditis, periauricular abscesses, and cervical adenitis in patients diagnosed with autosomal recessive variants of CGD [21
]. To our knowledge, our case is the first report of a pulmonary infection caused by S. viridans
in a patient with X-linked CGD.
The X-linked CGD-causing mutation identified in our patient was c.252 G>A, p.Ala84Ala, a mutation in the exon 3 of CYBB gene that affects splicing and lowers the expression of gp91-phox [6
]. The c.252 G>A mutation has been previously described using alternative nomenclature as c.264 G>A [6
]. This nucleotide substitution results in the replacement of codon Ala84 from GCG to GCA, both of which code for an alanine residue. Although this mutation does not change the predicted amino acid at this position, it prevents splicing of exon 3 to exon 4, causing exon 3 to be deleted in the patient's mRNA [11
]. It is proposed that the amino acid sequence encoded in exon 3 is essential for forming a necessary local tertiary structure in the first intracellular domain for p47phox binding and p22 interaction. Absence of this interaction seems to be detrimental to the stability of the enzyme complex [11
]. This mutation has been previously reported in late onset cases of CGD with residual reactive oxygen species (ROS) production [7
], although complete absence of NADPH oxidase activity has also been described [8
]. The mechanisms for which this phenotypic variability occurs are still unclear. It is possible that other genetic loci and/or other factors (i.e., epigenetic and environmental) may be implicated [11
]. Future research is required to conduct systematic correlations of clinical outcome, NAPDH functional data, and genetic mutations in order to better characterize specific subgroups of patients with CGD.
In summary, the clinical diagnosis of the mild forms of X-linked CGD may be extremely challenging and requires a high index of suspicion. For pediatric clinicians, information on the causative organism, severity, and location of the episodes, as well as pulmonary radiographic findings present, can provide critical diagnostic clues. Given that early therapy can improve survival in CGD, the prompt identification of atypical X-linked CGD variants with residual NADPH oxidase, in cases such as our patient, can significantly impact the clinical outcome of children with this condition.