Chronic granulomatous disease is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body from foreign invaders such as bacteria and fungi. Individuals with chronic granulomatous disease may have recurrent bacterial and fungal infections. People with this condition may also have areas of inflammation (granulomas) in various tissues that can result in damage to those tissues. The features of chronic granulomatous disease usually first appear in childhood, although some individuals do not show symptoms until later in life.

People with chronic granulomatous disease typically have at least one serious bacterial or fungal infection every 3 to 4 years. The lungs are the most frequent area of infection; pneumonia is a common feature of this condition. Individuals with chronic granulomatous disease may develop a type of fungal pneumonia, called mulch pneumonitis, which causes fever and shortness of breath after exposure to decaying organic materials such as mulch, hay, or dead leaves. Exposure to these organic materials and the numerous fungi involved in their decomposition causes people with chronic granulomatous disease to develop fungal infections in their lungs. Other common areas of infection in people with chronic granulomatous disease include the skin, liver, and lymph nodes.

Inflammation can occur in many different areas of the body in people with chronic granulomatous disease. Most commonly, granulomas occur in the gastrointestinal tract and the genitourinary tract. In many cases the intestinal wall is inflamed, causing a form of inflammatory bowel disease that varies in severity but can lead to stomach pain, diarrhea, bloody stool, nausea, and vomiting. Other common areas of inflammation in people with chronic granulomatous disease include the stomach, colon, and rectum, as well as the mouth, throat, and skin. Additionally, granulomas within the gastrointestinal tract can lead to tissue breakdown and pus production (abscesses). Inflammation in the stomach can prevent food from passing through to the intestines (gastric outlet obstruction), leading to an inability to digest food. These digestive problems cause vomiting after eating and weight loss. In the genitourinary tract, inflammation can occur in the kidneys and bladder. Inflammation of the lymph nodes (lymphadenitis) and bone marrow (osteomyelitis), which both produce immune cells, can lead to further impairment of the immune system.

Rarely, people with chronic granulomatous disease develop autoimmune disorders, which occur when the immune system malfunctions and attacks the body's own tissues and organs.

Repeated episodes of infection and inflammation reduce the life expectancy of individuals with chronic granulomatous disease; however, with treatment, most affected individuals live into mid- to late adulthood.

Mutations in the CYBA, CYBB, NCF1, NCF2, or NCF4 gene can cause chronic granulomatous disease. There are five types of this condition that are distinguished by the gene that is involved. The proteins produced from the affected genes are parts (subunits) of an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Specifically, NADPH oxidase is primarily active in immune system cells called phagocytes. These cells catch and destroy foreign invaders such as bacteria and fungi. Within phagocytes, NADPH oxidase is involved in the production of a toxic molecule called superoxide. Superoxide is used to generate other toxic substances, which play a role in killing foreign invaders and preventing them from reproducing in the body and causing illness. NADPH oxidase is also thought to regulate the activity of immune cells called neutrophils. These cells play a role in adjusting the inflammatory response to optimize healing and reduce injury to the body.

Mutations in the CYBA, CYBB, NCF1, NCF2, and NCF4 genes result in the production of proteins with little or no function or the production of no protein at all. Mutations in the genes that cause chronic granulomatous disease that prevent the production of any functional protein are designated "0". For example, mutations in the CYBB gene that lead to no functional beta chain are designated CYBB0. Mutations that lead to a reduction of the amount of protein produced are designated "-", for example, CYBB-.

Without any one of its subunit proteins, NADPH oxidase cannot assemble or function properly. As a result, phagocytes are unable to kill foreign invaders and neutrophil activity is not regulated. A lack of NADPH oxidase leaves affected individuals vulnerable to many types of infection and excessive inflammation.

Some people with chronic granulomatous disease do not have an identified mutation in any of these genes. The cause of the condition in these individuals is unknown.

Normal Function

The CYBA gene provides instructions for making a protein called the cytochrome b-245 alpha chain (also known as p22-phox). This protein is one part (subunit) of a group of proteins that forms an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Within this complex, the cytochrome b-245 alpha chain has a beta chain partner (produced from the CYBB gene). Both alpha and beta chains are required for either to function, and the NADPH oxidase complex requires both chains in order to be functional. NADPH oxidase is primarily active in immune system cells called phagocytes. These cells catch and destroy foreign invaders such as bacteria and fungi. NADPH oxidase is also thought to regulate the activity of immune cells called neutrophils. These cells play a role in adjusting the inflammatory response to optimize healing and reduce injury to the body.

The presence of foreign invaders stimulates phagocytes and triggers the assembly of NADPH oxidase. This enzyme participates in a chemical reaction that converts oxygen to a toxic molecule called superoxide. Superoxide is used to generate several other compounds, including hydrogen peroxide (a strong disinfectant) and hypochlorous acid (the active ingredient in bleach). These highly reactive, toxic substances are known as reactive oxygen species. Phagocytes use these substances to kill foreign invaders, preventing them from reproducing in the body and causing illness.

Health Conditions Related to Genetic Changes

Chronic granulomatous disease

More than 40 mutations in the CYBA gene have been found to cause chronic granulomatous disease. People with this disorder are at increased risk of developing recurrent episodes of infection and inflammation due to a weakened immune system. Mutations in the CYBA gene cause less than 5 percent of all cases of this condition. Most of these mutations change single building blocks of protein (amino acids) in the cytochrome b-245 alpha chain or cause it to be abnormally short and nonfunctional. An altered protein not only diminishes the function of the alpha chain, but the function of its beta chain partner as well. Without these subunits, NADPH oxidase cannot assemble or function properly. As a result, phagocytes are unable to produce reactive oxygen species to kill foreign invaders, and neutrophil activity is not regulated. A lack of NADPH oxidase leaves affected individuals vulnerable to many types of infection and excessive inflammation.

Other Names for This Gene

• CY24A_HUMAN
• cytochrome b light chain
• cytochrome b(558) alpha chain
• cytochrome b, alpha polypeptide
• cytochrome b-245 light chain
• cytochrome b-245, alpha polypeptide
• cytochrome b558 subunit alpha
• flavocytochrome b-558 alpha polypeptide
• neutrophil cytochrome b 22 kDa polypeptide
• p22phox
• superoxide-generating NADPH oxidase light chain subunit

Genomic Location

Normal Function

The CYBB gene provides instructions for making a protein called cytochrome b-245, beta chain (also known as p91-phox). This protein is one part (subunit) of a group of proteins that forms an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Within this complex, the cytochrome b-245, beta chain has an alpha chain partner (produced from the CYBA gene). Both alpha and beta chains are required for either to function and the NADPH oxidase complex requires both chains in order to be functional. NADPH oxidase is primarily active in immune system cells called phagocytes. These cells catch and destroy foreign invaders such as bacteria and fungi. NADPH oxidase is also thought to regulate the activity of immune cells called neutrophils. These cells play a role in adjusting the inflammatory response to optimize healing and reduce injury to the body.

The presence of foreign invaders stimulates phagocytes and triggers the assembly of NADPH oxidase. This enzyme participates in a chemical reaction that converts oxygen to a toxic molecule called superoxide. Superoxide is used to generate several other compounds, including hydrogen peroxide (a strong disinfectant) and hypochlorous acid (the active ingredient in bleach). These highly reactive, toxic substances are known as reactive oxygen species. Phagocytes use these substances to kill foreign invaders, preventing them from reproducing in the body and causing illness.

Health Conditions Related to Genetic Changes

Chronic granulomatous disease

More than 650 mutations in the CYBB gene have been found to cause chronic granulomatous disease. People with this disorder are at increased risk of developing recurrent episodes of infection and inflammation due to a weakened immune system. Mutations in the CYBB gene cause approximately 70 percent of all cases of this condition. Most of these mutations change single building blocks of protein (amino acids) in the cytochrome b-245 beta chain or cause it to be abnormally short and nonfunctional. An altered protein not only diminishes the function of the beta chain, but the function of its alpha chain partner as well. Without these subunits, NADPH oxidase cannot assemble or function properly. As a result, phagocytes are unable to produce reactive oxygen species to kill foreign invaders, and neutrophil activity is not regulated. A lack of NADPH oxidase leaves affected individuals vulnerable to many types of infection and excessive inflammation.

Other Names for This Gene

• CGD91-phox
• CY24B_HUMAN
• cytochrome b(558) subunit beta
• cytochrome b-245 heavy chain
• cytochrome b-245, beta polypeptide
• cytochrome b558 subunit beta
• GP91-1
• GP91PHOX
• neutrophil cytochrome b 91 kDa polypeptide
• p91-PHOX
• superoxide-generating NADPH oxidase heavy chain subunit

Genomic Location

Normal Function

The NCF1 gene provides instructions for making a protein called neutrophil cytosolic factor 1 (also known as p47-phox). This protein is one part (subunit) of a group of proteins that forms an enzyme complex called NADPH oxidase (NOX), which plays an essential role in the immune system. NOX is primarily active in immune system cells called phagocytes. These cells catch and destroy foreign invaders such as bacteria and fungi. NOX is also thought to regulate the activity of immune cells called neutrophils. These cells play a role in adjusting the inflammatory response to optimize healing and reduce injury to the body.

The presence of foreign invaders stimulates phagocytes and triggers the assembly of NOX. This enzyme participates in a chemical reaction that converts oxygen to a toxic molecule called superoxide. Superoxide is used to generate several other compounds, including hydrogen peroxide (a strong disinfectant) and hypochlorous acid (the active ingredient in bleach). These highly reactive, toxic substances are known as reactive oxygen species (ROS). Phagocytes use these substances to kill foreign invaders, preventing them from reproducing in the body and causing illness.

NOX plays a role in other cell types as well, such as blood vessel cells. Abnormal blood flow in blood vessels can trigger these cells to make more NOX, which stimulates the production of ROS. These compounds can influence blood pressure and other biological processes.

Health Conditions Related to Genetic Changes

Chronic granulomatous disease

Variants (also known as mutations) in the NCF1 gene account for about 25 percent of cases of chronic granulomatous disease. People with this disorder are at increased risk of developing recurrent episodes of infection and inflammation due to a weakened immune system. The variants that cause this disorder occur in both copies of the NCF1 gene in each cell. Ninety-five percent of affected individuals have a variant known as delta GT that deletes two DNA building blocks from the NCF1 gene in an area called exon 2 (written as 75_76delGT). This genetic change leads to the production of an abnormally short, nonfunctional version of neutrophil cytosolic factor 1. Other, less common variants also disrupt the function or production of neutrophil cytosolic factor 1. Without this protein, NOX cannot assemble or function properly. As a result, phagocytes are unable to produce ROS to kill foreign invaders, and neutrophil activity is not regulated. A lack of NOX leaves affected individuals vulnerable to many types of infection and excessive inflammation.

Williams syndrome

The NCF1 gene is located in a region of chromosome 7 that is often deleted in people with Williams syndrome. Williams syndrome is a developmental disorder that affects many parts of the body. As a result of the deletion of part of chromosome 7, some people with this condition are missing one copy of the NCF1 gene in each cell. Researchers have found that the loss of this gene is a protective factor that appears to lower the risk of developing high blood pressure (hypertension). People with Williams syndrome whose NCF1 gene is not deleted have a higher risk of developing hypertension.

People with only one copy of the NCF1 gene have reduced levels of the neutrophil cytosolic factor 1 protein, which decreases the activity of NOX and results in the production of fewer ROS. Studies suggest that ROS play an important role in blood vessel changes related to hypertension.

Other Names for This Gene

• NCF1_HUMAN
• p47-phox
• p47phox
• SH3PXD1A

Genomic Location

Normal Function

The NCF2 gene provides instructions for making a protein called neutrophil cytosolic factor 2 (also known as p67-phox). This protein is one part (subunit) of a group of proteins that forms an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Specifically, NADPH oxidase is primarily active in immune system cells called phagocytes. These cells catch and destroy foreign invaders such as bacteria and fungi. NADPH oxidase is also thought to regulate the activity of immune cells called neutrophils. These cells play a role in adjusting the inflammatory response to optimize healing and reduce injury to the body.

The presence of foreign invaders stimulates phagocytes and triggers the assembly of NADPH oxidase. This enzyme participates in a chemical reaction that converts oxygen to a toxic molecule called superoxide. Superoxide is used to generate several other compounds, including hydrogen peroxide (a strong disinfectant) and hypochlorous acid (the active ingredient in bleach). These highly reactive, toxic substances are known as reactive oxygen species. Phagocytes use these substances to kill foreign invaders, preventing them from reproducing in the body and causing illness.

Health Conditions Related to Genetic Changes

Chronic granulomatous disease

More than 50 mutations in the NCF2 gene have been found to cause chronic granulomatous disease. People with this disorder are at increased risk of developing recurrent episodes of infection and inflammation due to a weakened immune system. Mutations in the NCF2 gene cause less than 5 percent of all cases of this condition. These mutations change single protein building blocks (amino acids) in the neutrophil cytosolic factor 2 protein, which cause the protein to be abnormally short and nonfunctional or alter its 3-dimensional structure. All of these mutations decrease the function of the neutrophil cytosolic factor 2 protein or prevent its production. Without this protein, NADPH oxidase cannot assemble or function properly. As a result, phagocytes are unable to produce reactive oxygen species to kill foreign invaders and neutrophil activity is not regulated. A lack of NADPH oxidase leaves affected individuals vulnerable to many types of infection and excessive inflammation.

Systemic lupus erythematosus

Studies suggest that certain normal variations in the NCF2 gene can increase the risk of a condition called systemic lupus erythematosus. This condition is one of a group of related diseases known as autoimmune disorders, which occur when the immune system malfunctions and attacks the body's tissues and organs. The variants associated with increased risk of systemic lupus erythematosus change single DNA building blocks (nucleotides) in the NCF2 gene. These changes are thought to result in the production of a neutrophil cytosolic factor 2 protein with an altered function that impairs the function of NADPH oxidase. As a result, fewer reactive oxygen species are produced when foreign invaders trigger an immune reaction. This lack of reactive oxygen species causes the body to overcompensate by activating more immune cells and producing more immune proteins. The overactive immune reaction increases the risk that the immune cells will attack the body's tissues and organs, causing systemic lupus erythematosus. Researchers believe that a combination of genetic and environmental factors play a role in development of this complex condition.

Other Names for This Gene

• NADPH oxidase activator 2
• NCF-2
• NCF2_HUMAN
• neutrophil cytosol factor 2
• NOXA2
• P67-PHOX
• P67PHOX

Genomic Location

Normal Function

The NCF4 gene provides instructions for making a protein called neutrophil cytosolic factor 4 (also known as p40-phox). This protein is one part (subunit) of a group of proteins that forms an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Specifically, NADPH oxidase is primarily active in immune system cells called phagocytes. These cells catch and destroy foreign invaders such as bacteria and fungi. NADPH oxidase is also thought to regulate the activity of immune cells called neutrophils. These cells play a role in adjusting the inflammatory response to optimize healing and reduce injury to the body.

The presence of foreign invaders stimulates phagocytes and triggers the assembly of NADPH oxidase. This enzyme participates in a chemical reaction that converts oxygen to a toxic molecule called superoxide. Superoxide is used to generate several other compounds, including hydrogen peroxide (a strong disinfectant) and hypochlorous acid (the active ingredient in bleach). These highly reactive, toxic substances are known as reactive oxygen species. Phagocytes use these substances to kill foreign invaders, preventing them from reproducing in the body and causing illness.

Health Conditions Related to Genetic Changes

Chronic granulomatous disease

At least two mutations in the NCF4 gene have been found to cause chronic granulomatous disease. People with this disorder are at increased risk of developing recurrent episodes of infection and inflammation due to a weakened immune system. Mutations in the NCF4 gene are a rare cause of this condition. These mutations result in a decrease in functional NADPH oxidase. A shortage (deficiency) of this protein impairs the assembly or function of NADPH oxidase. As a result, phagocytes are unable to produce reactive oxygen species to kill foreign invaders, and neutrophil activity is not regulated. A lack of NADPH oxidase leaves affected individuals vulnerable to many types of infection and excessive inflammation.

Other Names for This Gene

• NCF
• NCF-4
• NCF4_HUMAN
• neutrophil cytosol factor 4
• neutrophil cytosolic factor 4, 40kDa
• neutrophil NADPH oxidase factor 4
• p40-phox
• P40PHOX

Genomic Location

• 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.

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.

Chronic granulomatous disease (CGD) is a genetic disorder in which white blood cells called phagocytes are unable to kill certain types of bacteria and fungi. People with CGD are highly susceptible to frequent and sometimes life-threatening bacterial and fungal infections.

CGD is a primary immune deficiency disease (PIDD).

Causes

CGD is caused by defects in an enzyme, NADPH oxidase, that phagocytes need to kill certain bacteria and fungi. Mutations in one of five different genes can cause these defects.

Symptoms & Diagnosis

People with CGD are highly susceptible to infections caused by certain bacteria and fungi, such as Staphylococcus aureus,Serratia marcescens, Burkholderia cepacia, Nocardia species, and Aspergillus species. These people may develop abscesses (boils) in their lungs, liver, spleen, bones, or skin; and masses of cells, called granulomas, that can obstruct the bowel or urinary tract. In some people, granulomas can cause an inflammatory bowel disease similar to Crohn’s Disease. In addition, heart or kidney problems, diabetes, and autoimmune disease may occur in people with CGD, but this varies depending on which gene is mutated.

CGD is diagnosed by special blood tests that show how well phagocytes produce hydrogen peroxide, an indicator that they are functioning properly.

Treatment

People with CGD take lifelong regimens of antibiotics and antifungals to prevent infections. Injections with interferon gamma, a protein that improves the activity of phagocytes, also may help reduce the number of severe infections. Abscesses need aggressive care that may include surgery. Granulomas may require steroid therapy. Some people with CGD have been treated successfully with bone marrow transplantation.

NIAID scientists are exploring gene therapy approaches to address the underlying genetic defects that cause CGD. In early 2017, they described using the CRISPR-Cas9 gene-editing strategy to correct the defective gene in cells taken from patients with the X-linked form of CGD.