X-chromosomale chronic granulomatosis D71.-

Janeway et al (1954) first described CGD in a patient with hypergammaglobulinemia associated with severe recurrent and chronic nonspecific infections, but without considering the disease as a distinct entity. Berendes et al (1957) and Bridges et al (1959) identified a "new syndrome" that they termed "fatal granulomatosis of childhood" (see Chronic Granulomatosis/Overview). Four boys had purulent lymphadenitis, hepatosplenomegaly, pulmonary infiltrates, and eczematous dermatitis, with granulomas noted in biopsy and autopsy specimens. Landing and Shirkey (1957) described 2 boys with recurrent infections who had infiltration of visceral organs by pigmented lipid histiocytes. Carson et al (1965) reported 16 men in 8 families with a syndrome of chronic suppurative lymphadenitis, chronic dermatitis, chronic lung disease, and hepatosplenomegaly with subsequent fatal outcome. Hypergammaglobulinemia was frequently present. Quie et al (1967) observed a form of fatal granulomatous disease in males in an X-linked pedigree. Leukocytes were able to phagocytose staphylococci normally but were impaired in their ability to digest the organism.

The estimated incidence of CGD in the United States is 1/200,000 births per year. Of 368 patients with CGD, approximately 76% had the X-linked recessive form (see further for septic granulomatosis).

X-linked chronic granulomatosis (CGD/progressive septic granulomatosis, X-linked) is a primary immunodeficiency disease characterized by phagocytic cell defects. The cause is a mutation in the CYBB gene.

X-linked chronic granulomatosis is a primary immunodeficiency characterized by the onset of symptoms in the first months or years of life. Patients present with recurrent infections, lymphadenopathy, inflammatory bowel disease, granulomatous colitis, fever, abscessed skin infections, osteomyelitis, and/or abscesses. Infectious organisms usually include Staphylococcus aureus, Burkholderia cepacia, Serrata, Salmonella, Mycobacteria and fungi. The disorder results from impaired function of the phagocytic NADPH oxidase complex, which is responsible for microbicidal production of reactive oxygen species. Due to a defect in microbicidal function, bacteria and fungi cannot be destroyed despite normal phagocytosis.

Laboratory studies using the DHR assay show impaired phagocytic production of reactive oxygen species in response to PMA stimulation (Dinauer et al. 2001; Song et al. 2014).

Secondary complications in patients with CGD include enteritis/colitis, urinary tract obstruction, discoid lupus, and chorioretinitis.

In a series of 6 males with CGD ranging in age from 2 to 22 years, Lischner and Martyn (1975) described chorioretinal lesions, sea-blue histiocytes, and changes that were misinterpreted as indicative of eosinophilic granuloma.

Dilworth and Mandell (1977) reported on four adult male siblings, aged 28, 30, 32, and 40 years, who developed severe bacterial infections of the lungs and lymph nodes at age 6 years. The sequelae included pulmonary fibrosis, unexplained polyarthritis, and glomerulonephritis. Despite normal morphology and the ability to take up microbes, the postphagocytic polymorphonuclear leukocytes were unable to reduce nitroblue tetrazolium (NBT), consume oxygen and produce hydrogen peroxide, and stimulate hexose monophosphate shunt. G6PD levels (305900) were normal. An intermediate quantitative NBT value in the mother of the brothers and in one daughter of each of two brothers suggests an X-linked recessive inheritance.

Bohler et al (1986) studied 25 patients with CGD. In 18 of 22 clinically typical cases, the complete inability of granulocytes to produce superoxide was associated with the absence of detectable cytochrome b. The mothers, but not the fathers, of these male patients showed decreased levels of cytochrome b. Flavoprotein deficiency detected in the granulocytes of 4 male patients was always associated with the absence of detectable cytochrome B. Three other patients had a mild form of X-linked CGD; the oxidative activity of their phagocytes and cytochrome B were decreased but not absent.

Southwick et al (1988) described recurrent episodes of severe cystitis in two unrelated men, aged 23 and 20 years, with X-linked CGD. Ultrasound showed large, inflammatory formations in the bladder that mimicked bladder carcinoma.

Song et al (2014) reported a 3-year-old boy who presented with recurrent persistent pneumonia that began at about 12 months of age. He had fever, oral ulcers, elevated C-reactive protein, abnormal liver enzymes, hepatomegaly, and lymphadenopathy. Nasal swabs showed respiratory syncytial virus (RSV) and blood showed Candida parapsilosis. Liver biopsy showed granuloma formation, and there was evidence of osteomyelitis. Laboratory studies of the patient's neutrophil granulocytes revealed that PMA stimulation produced few reactive oxygen species, suggestive of CGD. The boy received hematopoietic stem cell transplantation, which resulted in clinical improvement. Genetic analysis revealed a hemizygous missense mutation (D378G) in the CYBB gene inherited from the unaffected mother. Functional studies on this variant have not been performed.

Zurro et al (2018) reported a 20-year-old Brazilian male with CGDX. He had recurrent pneumonia, chronic colitis, and lymphadenopathy since 1.5 years of age. A lung biopsy at 3 years of age showed granulomatous lesions. He later developed abdominal pain associated with esophageal stenosis and was diagnosed with inflammatory bowel disease. At the age of 17 years, he developed severe pneumonia. Laboratory studies of the patient's neutrophil granulocytes revealed impaired reactive oxygen production after PMA stimulation compared with controls. The patient underwent stem cell transplantation with good outcome. Genetic analysis revealed a hemizygous missense mutation (V295E) in the CYBB gene.

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2. Bohler MC et al (1986) A study of 25 patients with chronic granulomatous disease: a new classification by correlating respiratory burst, cytochrome b and flavoprotein. J Clin Immun 6: 136-145.
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9. Song SM et al (2014) Identification of a novel mutation in the CYBB gene, p.Asp378Gly, in a patient with X-linked chronic granulomatous disease. Allergy Asthma Immun Res 6: 366-369.
10. Southwick FS et al.(1988) Recurrent cystitis and bladder mass in two adults with chronic granulomatous disease. Ann. Intern. Med 109: 118-121.
11. Zurro NB et al. (2018) A novel mutation in CYBB gene in a patient with chronic colitis and recurrent pneumonia due to X-linked chronic granulomatous disease. Pediat Blood Cancer 65: e27382.