Granulomatosis, septic D71.-

Approximately 76% of CGD (progressive septic granulomatosis) involves the X-linked recessive form with mutation in the CYBB gene.

Furthermore, this "phenotype" may be caused by mutations in other genes that also encode structural or regulatory subunits of the phagocyte NADPH oxidase complex. These include:

• CGD1 (233700), caused by mutation in the NCF1 gene (608512) on chromosome 7q11; 18% of cases.
• CGD2 (233710), caused by mutation in the NCF2 gene (608515) on chromosome 1q25; 4% of cases
• CGD3 (613960), caused by a mutation in the NCF4 gene (601488) on chromosome 22q13;
• CGD4 (233690), caused by a mutation in the CYBA gene (608508) on chromosome 16q24; 3% of cases
• CGD5 (618935), caused by a mutation in the CYBC1 gene (618334) on chromosome 17q25.

A similar syndrome, called neutrophil immunodeficiency syndrome (608203), is caused by a mutation in another protein involved in the NADPH oxidase complex (RAC2 /602049).

The estimated incidence of CGD in the United States is 1/200,000 births per year.

To date, defects in 4 chromosomes and thus of 4 components of NADPH oxidase have been identified as the cause of CGD.

In more than 50% of cases with CGD, the disease is inherited as an X-linked recessive trait and therefore occurs only in males. In the remaining cases, inheritance is autosomal recessive.

Most common are mutations in the CYBB gene (CYBB stands for "cytochrome B-245 beta chain" and is a protein coding gene located on chromosome Xp21.1-p11). Other affected genes are:

• p22PHOX-
• p47PHOX
• p67PHOX.

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

Patient survival has increased decisively since the introduction of lifelong continuous prophylaxis with the cell- and tissue-targeting cotrimoxazole. CGD granulocytes achieve limited bactericidal activity in the presence of cotrimoxazole, especially against staphylococci. Treatment consists of uniform prophylactic antibiotic doses, especially trimethoprim-sulfamethoxazole 160/800 mg p.o. 2 times/day. In cotrimoxazole allergy or G-6 PDH deficiency, trimethoprim in combination with rifampicin or ciprofloxacin can be tried.

In severe infections, granulocyte transfusions.

Hematopoietic stem cell transplantation.

Oral antifungals are given as primary prophylaxis or added if fungal infections occur even once; most useful are

• Itraconazole p.o. every 12 h (100 mg for patients <13 years of age, 200 mg for those ≥ 13 years of age or weighing > 50 kg)
• Voriconazole p.o. every 12 h (100 mg for those weighing <40 kg; 200 mg for those weighing ≥ 40 kg)
• Posaconazole (400 mg twice daily).

Interferon-gammamay reduce the severity and frequency of infections and is usually added to treatment. The usual dose is 50 μg/m2 subcutaneously 3 times/week.

In severe infections, granulocyte transfusions may be life-saving.

If transplantation is preceded by chemotherapy, human leukocyte antigen-identical hemotopoietic stem cell transplantation from siblings is usually successful.

Gene therapy is being investigated in current trials.

1. Berendes H et al (1957) A fatal granulomatous disease of childhood. The clinical study of a new syndrome. Minn Med 40: 309-312
2. Kamani NR et al (2000) Chronic granulomatous disease and other disorders of neutrophil function. Clin Rev Allergy Immunol 19: 141-156