Chronic granulomatous disease

Other Names: Granulomatous disease, chronic

Chronic granulomatous disease (CGD) is a rare, inherited immunodeficiency that affects certain white blood cells. People with this condition have immune systems that do not function properly, leaving the body vulnerable to chronic inflammation and frequent bacterial and fungal infections. The features of this condition usually develop in infancy or early childhood; however, milder forms may be diagnosed in the teen years or even in adulthood.

Two neutrophils among many red blood cells. Neutrophils are one type of cell affected by chronic granulomatous disease.

Inheritance

Autosomal recessive inheritance, a 25% chance

It is caused by changes (mutations) in any one of five different CYBA, NCF1, NCF2, or NCF4 genes, and is usually inherited in an autosomal recessive or X-linked recessive manner.

This means that a person must have a change in both copies of the disease-causing gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

X-linked recessive inheritance

When chronic granulomatous disease is caused by mutations in the CYBB gene, the condition is inherited in an X-linked recessive pattern. The CYBB gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one mutated copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two mutated copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. Rarely, females with one mutated copy of the CYBB gene have mild symptoms of chronic granulomatous disease, such as an increased frequency of bacterial or fungal infections.

Symptoms

In people with chronic granulomatous disease, the immune system does not work properly, which leaves the body vulnerable to certain types of bacteria and fungi. The signs and symptoms vary but may include:

• Frequent bacterial and fungal infections
• Granulomas (areas of inflamed tissue), most commonly in the gastrointestinal tract and/or the genitourinary system
• Abscesses that involve the lungs, liver, spleen, bones, or skin
• Swollen lymph nodes
• Persistent diarrhea
• Chronic runny nose.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of neutrophils
• Chronic obstructive pulmonary disease
• Cutaneous photosensitivity(Photosensitive skin)
• Fever
• Hepatomegaly(Enlarged liver)
• Hypermelanotic macule(Hyperpigmented spots)
• Malabsorption(Intestinal malabsorption)
• Mediastinal lymphadenopathy(Swollen lymph nodes in center of chest)
• Otitis media(Middle ear infection)
• Pyloric stenosis
• Recurrent respiratory infections(Frequent respiratory infections)
• Sinusitis(Sinus inflammation)
• Tracheoesophageal fistula

5%-29% of people have these symptoms

• Eczema
• Gingivitis
• Inflamed gums
• Inflammatory abnormality of the eye
• Liver abscess
• Meningitis
• Sepsis(Infection in blood stream)
• Skin ulcer(Open skin sore)
• Splenomegaly(Increased spleen size)

Cause

Chronic granulomatous disease is caused by changes (mutations) in one of five genes (CYBA, CYBB, NCF1, NCF2, or NCF4). Each gene encodes a different part (subunit) of an enzyme called NADPH oxidase, which is essential to the immune system One function of this enzyme is to help make toxic substances that are used to kill bacteria and fungi that invade the body before they can cause infection. It may also play a role in regulating the activity of immune cells that help manage the inflammatory response.

Mutations in these genes lead to reduced levels of NADPH oxidase and in severe cases, no enzyme is produced. As a result, the immune system can not function properly, leaving the body vulnerable to frequent infections and chronic inflammation.

Diagnosis

A diagnosis of chronic granulomatous disease is often suspected based on the presence of characteristic signs and symptoms. Specialized blood tests, such as the nitroblue tetrazolium test and/or flow cytometry with dihydrorhodamine, can then be ordered to confirm the diagnosis. Both of these tests can be used to determine whether or not the immune cells are making toxic substances that the body uses to fight infections.

The diagnosis of CGD is established with identification of the mutation(s) in one of five genes: CYBA, NCF1, NCF2, and NCF4 (the genes related to autosomal recessive chronic granulomatous disease) CYBB is the gene related to the X-linked chronic granulomatous disease.

Treatment

Chronic granulomatous disease is usually managed with antibiotic and antifungal medications to treat and prevent infection. Corticosteriods may be used to shrink granulomas (areas of inflamed tissue). Treatment may also include a medication called Actimmune (also known as interferon gamma-1b). Actimmune is a man-made version of a substance normally produced by the body's immune cells and has been shown to decrease the frequency of severe infections in people with chronic granulomatous disease.

Early diagnosis of infection is very important, so people with chronic granulomatous disease are generally followed closely by a medical professional. The frequency of follow-up will depend on the severity of the condition.

A bone marrow transplant (allogeneic hematopoietic stem cell transplantation or HSCT) may be used to treat and possibly cure chronic granulomatous disease

Medical researchers believe gene therapy also holds great promise as a future cure, but more clinical studies are needed to determine if gene therapy will be both safe and effective for those with chronic granulomatous disease. As medical researchers better understand chronic granulomatous disease, new treatments that help control the immune system (immunomodulatory agents) may also become available. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Interferon gamma-1b (Brand name: Actimmune®)

Prognosis

The average person with chronic granulomatous disease now survives at least 40 years, due in large part to routine use of prophylactic therapies.

Chronic granulomatous disease Resources
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NIH genetic and rare disease info

• NIH info on Chronic granulomatous disease

Chronic granulomatous disease is a rare disease.