A number sign (#) is used with this entry because of evidence that autosomal recessive chronic granulomatous disease-5 (CGD5) is caused by homozygous mutation in the CYBC1 gene (618334) on chromosome 17q25.

Autosomal recessive chronic granulomatous disease-5 (CGD5) is a primary immunodeficiency characterized by onset of recurrent infections and severe colitis in the first decade of life. Patients often present with features of inflammatory bowel disease and may show granulomata on biopsy. Patients are particularly susceptible to catalase-positive organisms, including Burkholderia cepacia, Legionella, and Candida albicans. Some patients may develop autoinflammatory symptoms, including recurrent fever in the absence of infection, hemolytic anemia, and lymphopenia. Additional features may include short stature, viral infections, cutaneous abscesses, pulmonary infections, and lymphadenitis. Hematopoietic bone marrow transplant is curative. The disorder results from impaired oxidative burst via the NAPDH oxidative complex in macrophages and neutrophils (summary by Arnadottir et al., 2018 and Thomas et al., 2019).

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

Monies et al. (2017) and Thomas et al. (2019) reported a boy, born of Saudi Arabian parents, with CGD5 and evidence of autoimmune disease. He first presented in infancy with a localized abscess following BCG vaccination. He was well until about 8 years, but had growth retardation, short stature, and recurrent pulmonary infections with tonsillitis, pharyngitis, and lymphadenopathy. He later developed febrile episodes associated with elevated inflammatory markers, hemolytic anemia, and lymphopenia. Additional features included declining pneumococcal antibody responses, declining immunoglobulin levels, hepatosplenomegaly, and granulomata in his lungs and bone marrow. Patient neutrophils showed impaired respiratory burst activity compared to controls. He underwent bone marrow transplant and recovered well.

Arnadottir et al. (2018) reported 2 Icelandic brothers with CGD5. The boys were initially diagnosed with Crohn disease at 7 and 9 years of age after intestinal biopsies showed granulomatous lesions. Both had recurrent infections, including skin infections, otitis media, oral or orbital infections, lymphadenitis, viral infections, and pneumonia. Many of the infectious agents were catalase-positive pathogens. Specific organisms identified included Burkholderia cepacia, Legionella, C. difficile, and Candida albicans. Each patient also had an episode of acute pancreatitis. Laboratory studies showed impaired PMA-induced neutrophil oxidative burst, consistent with a diagnosis of CGD. Both patients underwent hematopoietic stem cell transplantation at 17 and 18 years of age. The older brother died of complications, whereas the younger brother had a successful transplant and remained symptom-free. Subsequently, the authors identified 6 additional Icelandic patients with a similar disorder. Three were diagnosed with inflammatory bowel disease, including Crohn disease and ulcerative colitis; granulomatous colitis was confirmed in 2 patients. One patient had a total colectomy. Five of these 6 additional patients had notable infections, including Herpes, acne, invasive pneumococcal disease, and miliary tuberculosis. More variable features included eczema, chronic tonsillitis, and interstitial pulmonary disease with fibrosis. One patient had a positive rheumatoid factor. Neutrophil burst test, performed in 1 patient, was abnormal. Many of the patients were short of stature.

The transmission pattern of CGD5 in the family reported by Arnadottir et al. (2018) was consistent with autosomal recessive inheritance.

In a patient, born of Saudi Arabian parents, with CGD5, Monies et al. (2017) and Thomas et al. (2019) identified a homozygous splice site mutation in the CYBC1 gene (618334.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Western blot analysis of patient T cells showed undetectable CYBC1 protein levels, and patient neutrophils showed impaired respiratory burst activity, consistent with a functional defect in NADPH oxidase.

In 2 Icelandic brothers with CGD5, Arnadottir et al. (2018) identified a homozygous nonsense mutation in the CYBC1 gene (Y2X; 618334.0002). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Further analysis of the large Icelandic dataset identified 6 additional patients with a similar phenotype who were homozygous for Y2X. Western blot analysis of lymphocytes derived from 2 patients showed absence of the full-length protein. Functional studies showed strongly impaired PMA-induced oxidative burst in neutrophils from 1 patient. The frequency of the variant in Iceland was estimated to be 1 in 70, consistent with a founder effect.