What is chronic granulomatous disease?

Risk Factors

Individuals whose parents have the recessive trait and females have an increased chance of developing CGD.

Etiology and Genetics

Mutations in at least four different genes have been identified that can result in clinical symptoms that are recognized as CGD. The most common form (50–70 percent of all cases) involves a mutation in the CYBB gene, found on the short arm of the X chromosome at position Xp21.1. This gene encodes the b subunit of cytochrome B, one of the essential protein complexes of the electron transport system found in mitochondria. The inheritance pattern of this disease is typical of all sex-linked recessive mutations (those found on the X chromosome). Mothers who carry the mutated gene on one of their two X chromosomes face a 50 percent chance of transmitting this disorder to each of their male children. Female children have a 50 percent chance of inheriting the gene and becoming carriers like their mothers. Although females rarely express the syndrome fully, female carriers may occasionally show minor manifestations. Affected males will pass the mutation on to all of their daughters but to none of their sons.

An autosomal recessive form of the disease accounts for approximately 20–40 percent of all cases, and this results from a mutation in the NCF1 gene, found on the long arm of chromosome 7 at position 7q11.23. The protein product of this gene is known as neutrophil cytosolic factor-1, an important component of the NADPH oxidase complex. In autosomal recessive inheritance, both copies of a particular gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has CGD and the other is a carrier, there is a 50 percent probability that each child will be affected.

The remaining 10 percent of cases of CGD result from mutations in either of two additional autosomal genes, and both of these are also inherited in a classic autosomal recessive manner. The NCF2 gene, which encodes neutrophil cytosolic factor-2, is found at position 1q25 on the long arm of chromosome 1, and the CYBA gene, which specifies a subunit of cytochrome B, is located on the long arm of chromosome 16 at position 16q24.

Symptoms

Symptoms typically begin to appear in childhood. In some patients, they may not appear until the teen years. Symptoms include swollen lymph nodes in the neck and abscesses in the neck’s lymph nodes or liver. Other symptoms of CGD are frequent skin infections that are resistant to treatment, such as chronic infections inside the nose; impetigo (a bacterial skin infection); abscesses; furuncles (boils); eczema worsened by an infection; and abscesses near the anus. Frequent pneumonia that is resistant to treatment, persistent diarrhea, infections of the bones, infections of the joints, and fungal infections are additional symptoms.

Screening and Diagnosis

The doctor will ask about a patient’s symptoms and medical history, and a physical exam will be done. Tests may include a biopsy, the removal of a sample of tissue to test for the condition; a dihydrorhodamine reduction (DHR) flow cytometry test, a blood test that looks at the ability of phagocytes to make chemicals that can destroy bacteria; an erythrocyte sedimentation rate (ESR) to test for inflammation; a chest X ray, a test that uses radiation to take pictures of structures inside the chest cavity; a bone scan; a liver scan; and a complete blood count (CBC).

Treatment and Therapy

Patients should talk with their doctors about the best plans for them. Treatment options include medications, such as antibiotics and interferon gamma. Antibiotics are used for preventive and fungal treatments and for new infections. Interferon gamma reduces the number of infections in patients, but it is not useful in acute (newly active) infections.

A bone marrow transplantation may be an option. A suitable donor will need to be found. It is a definitive cure. Surgery to treat CGD may involve the debridement or removal of abscesses.

Patients should avoid some live viral vaccines and should consult with an immunologist before receiving one.

Prevention and Outcomes

CGD is an inherited disease. There are no preventive steps to reduce the risk of being born with the disease. Genetic counseling may be helpful; it can be used to detect carrier status in women. Early diagnosis is essential and will allow for early treatment. The bone marrow transplant donor search can also be started.

Bibliography

Bernhisel-Broadbent, J., et al. “Recombinant Human Interferon-Gamma as Adjunct Therapy for Aspergillus Infection in a Patient with Chronic Granulomatous Disease.” Journ. of Infectious Diseases 163.4 (1991): 908–11. Print.

Dinauer, M. C., J. A. Lekstrom-Himes, and D. C. Dale. “Inherited Neutrophil Disorders: Molecular Basis and New Therapies.” Hematology: The Education Program of the American Society of Hematology (2000): 303–18.

Lekstrom-Himes, J. A., and J. I. Gallin. “Immunodeficiency Diseases Caused by Defects in Phagocytes.” New England Journ. of Medicine 343.23 (2000): 1703–14.

Miranda, Roberto N., Joseph D. Khoury, and L. Jeffrey Medeiros. Atlas of Lymph Node Pathology. New York: Springer, 2013. Print.

Pogrebniak, H. W., et al. “Surgical Management of Pulmonary Infections in Chronic Granulomatous Disease of Childhood.” Annals of Thoracic Surgery 55.4 (1993): 844–49.

Rawat, Amit. "Chronic Granulomatous Disease: Two Decades of Experience from a Tertiary Care Centre in North West India." Journ. of Clinical Immunology 43.1 (2014): 58–67. Print.

Roos, D., and M. Boer. "Molecular Diagnosis of Chronic Granulomatous Disease." Clinical & Experimental Immunology 175.2 (2014): 139–49. Print.