Chronic granulomatous disease

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Disease Profile

1-9 / 1 000 000

331-2,979

US Estimated

513-4,622

Europe Estimated

Age of onset

Infancy

ICD-10

D71

Inheritance

When chronic granulomatous disease is caused by changes (mutations) in the CYBA, NCF1, NCF2, or NCF4 genes, it is inherited in an autosomal recessive manner.^[5]^[3] 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.

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.^[3]

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Granulomatous disease, chronic

Summary

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.^[1]^[2] It is caused by changes (mutations) in any one of five different genes and is usually inherited in an autosomal recessive or X-linked recessive manner.^[3] Treatment consists of continuous therapy with antibiotic and antifungal medications to treat and prevent infections.^[1]^[4] The only cure for the disease is an allogeneic hematopoietic stem cell transplantation (HSCT).^[5]

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 features of the condition usually develop in infancy or early childhood; however, milder forms may be diagnosed in the teen years or even in adulthood. The signs and symptoms vary but may include:^[1]^[2]^[3]

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.

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms	Other Names	Learn More: HPO ID
80%-99% of people have these symptoms
Abnormality of neutrophils		0001874
Chronic pulmonary obstruction		0006510
Cutaneous photosensitivity	Photosensitive skin Photosensitive skin rashes Photosensitivity Sensitivity to sunlight Skin photosensitivity Sun sensitivity [ more ]	0000992
Fever		0001945
Hepatomegaly	Enlarged liver	0002240
Hypermelanotic macule	Hyperpigmented spots	0001034
Malabsorption	Intestinal malabsorption	0002024
Mediastinal lymphadenopathy	Swollen lymph nodes in center of chest	0100721
Otitis media	Middle ear infection	0000388
Pyloric stenosis		0002021
Recurrent respiratory infections	Frequent respiratory infections Multiple respiratory infections respiratory infections, recurrent Susceptibility to respiratory infections [ more ]	0002205
Sinusitis	Sinus inflammation	0000246
Tracheoesophageal fistula		0002575
5%-29% of people have these symptoms
Eczema		0000964
Gingivitis	Inflamed gums Red and swollen gums [ more ]	0000230
Inflammatory abnormality of the eye		0100533
Liver abscess		0100523
Meningitis		0001287
Sepsis	Infection in blood stream	0100806
Skin ulcer	Open skin sore	0200042
Splenomegaly	Increased spleen size	0001744

Do you have updated information on this disease? We want to hear from you.

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.^[3]

For background information on how the body naturally responds to invading bacteria, visit the link about the immune system offered by the National Institute of Allergy and Infectious Diseases (NIAID).

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.^[1]^[2]

The diagnosis of CGD is established with identification of the mutation(s) in one of five genes:[12468]

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.

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

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.^[1]^[2]^[4]^[5]^[6]

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.^[1]^[2]^[4]

A bone marrow transplant (allogeneic hematopoietic stem cell transplantation or HSCT) may be used to treat and possibly cure chronic granulomatous disease, however HSCT has serious risks including the possibility of severe disability or death. Although the risks associated with HSCT are decreasing due to medical advances, HSCT is usually only considered for those severely affected by chronic granulomatous disease.^[1]^[2]^[4]^[5]

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.^[4]^[5] As medical researchers better understand chronic granulomatous disease, new treatments that help control the immune system (immunomodulatory agents) may also become available.^[6]

FDA-Approved Treatments

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition. Learn more orphan products.

Interferon gamma-1b(Brand name: Actimmune®) Manufactured by InterMune , Inc.
FDA-approved indication: Treatment of chronic granulomatous disease.
National Library of Medicine Drug Information Portal

Related diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes cystic fibrosis, Crohn disease, hyper-IgE syndrome, allergic bronchopulmonary aspergillosis, glutathione synthetase deficiency, and secondary hemophagocytic lymphohistiocytosis (see these terms). Myeloperoxidase deficiency (see this term) must also be excluded, as it gives a false positive for the DHR assay test. Visit the Orphanet disease page for more information.

Conditions with similar signs and symptoms from Orphanet

Differential diagnosis includes cystic fibrosis, Crohn disease, hyper-IgE syndrome, allergic bronchopulmonary aspergillosis, glutathione synthetase deficiency, and secondary hemophagocytic lymphohistiocytosis (see these terms). Myeloperoxidase deficiency (see this term) must also be excluded, as it gives a false positive for the DHR assay test.

Visit the Orphanet disease page for more information.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

CGD Association of America (CGDAA)
2005 Palmer Avenue #197
Larchmont, NY 10538
E-mail: info@cgdaa.org
Website: https://www.cgdaa.org/
CGD Society
PO Box 454
Dartford, DA1 9PE United Kingdom
Telephone: 0800 987 8988
E-mail: hello@cgdsociety.org
Website: https://cgdsociety.org/

Organizations Providing General Support

Immune Deficiency Foundation
110 West Road, Suite 300
Towson, MD 21204
Toll-free: 1-800-296-4433
Fax: +1-410-321-9165
E-mail: https://www.primaryimmune.org/services/ask-idf/
Website: https://www.primaryimmune.org/
Primary Immune Deficiency UK (PID UK)
PO Box 6970
Basingstoke, RG24 4XL United Kingdom
Toll-free: 0800 987 8986
E-mail: hello@piduk.org
Website: https://www.piduk.org/

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The CGD Society has an information page on Chronic granulomatous disease. Please click the link to access this resource.
MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
MedlinePlus Genetics contains information on Chronic granulomatous disease. This website is maintained by the National Library of Medicine.
The Merck Manuals Online Medical Library provides information on this condition for patients and caregivers.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Merck Manual for health care professionals provides information on Chronic granulomatous disease.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) lists the subtypes and associated genes for Chronic granulomatous disease in a table called Phenotypic Series. Each entry in OMIM includes a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Chronic granulomatous disease. Click on the link to view a sample search on this topic.

References

Nowicki RJ. Chronic Granulomatous Disease. Medscape Reference. 2018; https://emedicine.medscape.com/article/1116022-overview.
Chronic Granulomatous Disease. NORD. 2018; https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/682/viewAbstract.
Chronic Granulomatous Disease. MedlinePlus Genetics. 2016; https://medlineplus.gov/genetics/condition/chronic-granulomatous-disease/.
Rosenzweig SD & Holland SM. Chronic granulomatous disease: Treatment and prognosis. UpToDate. 2018; https://www.uptodate.com/contents/chronic-granulomatous-disease-treatment-and-prognosis.
Leiding JW & Holland SM. Chronic Granulomatous Disease. GeneReviews. February 11, 2016; https://www.ncbi.nlm.nih.gov/books/NBK99496/.
Vignesh P, Rawat A & Singh S. An Update on the Use of Immunomodulators in Primary Immunodeficiencies. Clin Rev Allergy Immunol.. Nov 21 2016; [Epub ahead of print]:https://www.ncbi.nlm.nih.gov/pubmed/27873163.

Rare Medical News

Rare Medical News

Rare Medical News

Infancy

D71

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Other names (AKA)

Categories

Summary

Symptoms

Cause

Diagnosis

Testing Resources

Treatment

FDA-Approved Treatments

Related diseases

Organizations

Organizations Supporting this Disease

Organizations Providing General Support

Learn more

Where to Start

In-Depth Information

References

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.