A number sign (#) is used with this entry because of evidence that autosomal recessive chronic granulomatous disease-3 (CGD3) is caused by homozygous or compound heterozygous mutation in the NCF4 gene (601488), which encodes the p40-phox (phagocyte oxidase) protein, on chromosome 22q12. P40-phox is a subunit of the NADPH oxidase complex.

Autosomal recessive chronic granulomatous disease-3 (CGD3) is an immunodeficiency disorder characterized by recurrent pyogenic infections and granulomatous inflammation with onset usually in the first decade of life. Most patients present with colitis and features of inflammatory bowel disease. Other common manifestations include lupus-like skin lesions, skin granulomas, Staphylococcal abscesses, oral ulcers, and periodontitis. Patients usually do not have invasive infections and are not markedly susceptible to fungal infections. The disorder results from variable loss of phagocyte superoxide production due to NADPH oxidase dysfunction; it is generally less severe than other genetic types of CGD (summary by Matute et al., 2009; van de Geer et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of CGD, see the X-linked form (CGDX; 306400).

Matute et al. (2009) reported a 3.5-year-old boy who presented with diarrhea, low-grade fever, and perianal rash. He also had perioral eczema and aphthous ulcers. He was found to have chronic granulomatous colitis, with erosions and ulceration of the gastric fundus and colonic mucosa, and multiple small granulomata on colonic biopsy. He had a history of eczema, sinusitis, and recurrent croup. His parents were unaffected. Studies of patient neutrophils showed a selective and substantial defect in NADPH oxidase activity and intracellular superoxide production during phagocytosis. However, extracellular oxidant production in response to soluble agonists was normal. Matute et al. (2009) noted that this patient had not had infections with opportunistic pathogens characteristic of other forms of chronic granulomatous disease.

Van de Geer et al. (2018) reported 24 patients from 12 families with CGD3 confirmed by genetic analysis. The families originated from several different countries, including Pakistan, Portugal, Australia, Colombia, Russia, Chile, Kuwait, and Argentina. Five families, including 4 from Pakistan and 1 from Kuwait, were consanguineous. Features among symptomatic individuals were variable, but commonly included recurrent peripheral, usually non invasive infections and hyperinflammation, such as chronic fever. Most patients had onset of symptoms in the first decade, although 3 had onset in the teenage years (11 to 17 years). Four individuals with biallelic NCF4 mutations, who ranged in age from 1 to 10 years, were asymptomatic. Features in symptomatic patients included inflammatory bowel disease with colonic or esophageal granulomata and ulcerations, anal fistula, oral thrush or mucosal lesions, recurrent skin abscesses with Staphylococcus infection, lupus-like skin lesions, eczema, lymphadenitis, blepharitis or conjunctivitis, periodontitis, and recurrent respiratory infections with interstitial inflammation. Invasive infections were rare, but 1 patient had recurrent disseminated histoplasmosis. Most patients received BCG vaccination with no adverse effects. Most patients were negative for autoantibodies, although a few had antinuclear Abs (ANAs) or antineutrophil cytoplasmic Abs (ANCAs). One patient had a total colectomy, and 4 underwent hematopoietic stem cell transplantation. None of the patients had died. PMA-induced DHR oxidation was normal or only mildly impaired. Van de Geer et al. (2018) concluded that CGD3 represents a milder atypical form of CGD compared to the other genetic types.

The transmission pattern of CGD3 in the families reported by van de Geer et al. (2018) was consistent with autosomal recessive inheritance with incomplete or age-dependent penetrance.

In a boy with CGD3, Matute et al. (2009) identified compound heterozygous mutations in the NCF4 gene (10-bp dup, 601488.0001 and R105Q, 601488.0002). In vitro studies of patient neutrophils showed impaired intracellular oxidant production during phagocytosis of serum opsonized S. aureus, although PMA-stimulated superoxide release was normal. Matute et al. (2009) noted that genomewide association studies (Rioux et al., 2007) had identified a SNP in the NCF4 gene (rs4821544) that was associated with Crohn disease, suggesting that there may be a relationship between NCF4, phagocytosis-induced oxidant production, and predisposition to inflammatory bowel disease (see IBD, 266600).

In 24 patients from 12 families of various ethnic origins with CGD3, van de Geer et al. (2018) identified homozygous or compound heterozygous mutations in the NCF4 gene (see, e.g., 601488.0002-601488.0006). The mutations, which were found by exome sequencing or targeted panel sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There was evidence of age-dependent or incomplete penetrance in 2 families. Mutation types included missense, nonsense, splice site, and a small in-frame deletion. They occurred throughout the gene and all but 1 were absent from the gnomAD database. In vitro functional expression studies in patient-derived cells and EBV-transformed B cells expressing the mutations showed variably impaired production of reactive oxygen species (ROS), indicating dysfunction of the NADPH oxidase complex and a loss-of-function effect. The functional impact depended on the phagocytic cell type and stimulus. Neutrophils and EBV-transformed B cells carrying the mutations showed impaired NADPH oxidase activity. Neutrophils were ineffective against Staphylococcus, had variable activity against E. coli, and retained almost normal defense against fungi. In contrast, NADPH oxidase activity in mononuclear phagocytes was similar to controls. PMA-induced DHR oxidation was normal or only mildly impaired in certain cell types and conditions, reflecting impaired, but not abolished, ROS production.

Ellson et al. (2006) generated p40-phox -/- mice, which were healthy and fertile when kept under pathogen-free barrier conditions. Neutrophils of p40-phox -/- mice showed reduced expression of p67-phox and diminished oxidase responses to a number of stimuli. Defective reactive oxygen species production by p40-phox -/- neutrophils in response to Staphylococcus aureus translated into a severe, CGD-like defect in the killing of this organism in vitro and in vivo. Ellson et al. (2006) concluded that p40-phox is an essential component in bacterial killing.