Chronic Granulomatous Disease, X-linked
Table of Contents
Other Names for This Condition
- Autosomal recessive chronic granulomatous disease
- Granulomatous disease, chronic
- X-linked chronic granulomatous disease
In vitro fertilization (IVF) and preimplantation genetic testing (PGT) are significant advancements in the realm of reproductive medicine and genetics, particularly for individuals at risk of transmitting genetic disorders like Chronic Granulomatous Disease, X-linked. For couples with a known risk of passing on Chronic Granulomatous Disease, X-linked to their offspring, IVF coupled with PGT offers a proactive approach. In this process, eggs are fertilized in a lab setting, and the resulting embryos are screened for the specific genetic mutations associated with Chronic Granulomatous Disease, X-linked. This enables the selection of embryos without the disorder for implantation, significantly reducing the likelihood of the child inheriting Chronic Granulomatous Disease, X-linked. Thus, IVF and PGT provide a powerful combination for family planning, particularly for those with a genetic predisposition to this condition, allowing them to minimize the risk of genetic transmission while achieving pregnancy.
Chronic granulomatous disease (CGD) is a hereditary condition that disrupts normal immune system function, leading to immunodeficiency. Such deficiencies hinder the immune system’s ability to defend against external pathogens like bacteria and fungi. Those affected by CGD often suffer from repeated infections caused by these organisms. Additionally, they can develop granulomas—clusters of inflammation in various body tissues, which can cause tissue damage. Typically, signs of CGD emerge during childhood, but in some cases, symptoms may not manifest until adulthood.
CGD is considered rare, with an estimated incidence of 1 in 250,000 live births. It stems from mutations in one of the five subunits of the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase found in phagocytes. This enzyme is crucial for producing superoxide, a substance vital for the phagocytes’ ability to kill pathogens internally.
As a fundamental immunodeficiency, CGD impairs the innate immune system’s phagocytes, leading to repeated and enduring infections by intracellular bacteria and fungi, as well as the formation of granulomas. About two-thirds of those with CGD experience their initial symptoms within the first year of life, including infections, dermatitis (which may be present from birth), gastrointestinal issues (such as blockages or intermittent bloody diarrhea due to colitis), and poor growth. The severity of these symptoms varies significantly from one infant to another; some experience multiple issues while others seem less affected. Skin diseases are present in 60-70% of individuals with CGD. Recently, Rasamsonia species have been recognized as a rising threat within this group.
The global incidence of Chronic Granulomatous Disease (CGD) is estimated to affect roughly 1 in 200,000 to 250,000 individuals. The estimated prevalence at birth for CGD varies globally between 1 in 100,000 to 1 in 217,000 individuals. In the United States, the reported occurrence rate of CGD, based on retrospective and voluntary data, is about 1 in 200,000 live births.
Symptoms of CGD usually present early in life, but there are cases where the diagnosis is made during later stages. Commonly, individuals with CGD experience repeated bacterial infections starting in infancy. However, in some cases, these symptoms may not emerge until the individual reaches 10 to 20 years of age.
Individuals with chronic granulomatous disease (CGD) often experience severe bacterial or fungal infections approximately every three to four years. The most commonly affected area is the respiratory system, with pneumonia being a frequent manifestation of CGD. A specific type of pneumonia known as “mulch pneumonitis” is also seen in CGD, characterized by fever and difficulty breathing following exposure to decomposing organic matter, which harbors fungi that can lead to lung infections.
Infections in CGD are not limited to the lungs; the skin, liver, and lymphatic system are also vulnerable. In addition to infections, widespread inflammation is a hallmark of CGD, particularly granuloma formation in the digestive and genitourinary systems. This can lead to symptoms akin to inflammatory bowel disease, including abdominal pain, diarrhea, bloody stools, and nausea, with varying degrees of severity. The inflammation can also affect the mouth, esophagus, and skin, and when granulomas form in the gastrointestinal tract, they can cause abscesses, disrupt tissue integrity, and, in cases involving the stomach, obstruct the passage of food, causing vomiting and weight loss. Inflammation of the kidneys, bladder, lymph nodes, and bone marrow can further compromise the immune response.
Although less common, some individuals with CGD may develop autoimmune disorders, adding to the complexity of the disease. Infection and inflammation cycles can impact longevity in CGD patients, but with appropriate medical care, many live into their middle to late years of adulthood.
Chronic granulomatous disease (CGD) can be triggered by mutations in any one of several genes: CYBA, CYBB, NCF1, NCF2, or NCF4. Each of these genes is responsible for encoding a different subunit of the NADPH oxidase enzyme complex, which is critical for immune system function, particularly in phagocytes. When mutations occur the resulting proteins may be dysfunctional or not produced at all.
In North America and Western Europe, mutations in the CYBB gene account for 65% of CGD cases, which is located on the X chromosome. The remaining 35% of cases are associated with mutations in the CYBA, NCF1, NCF2, NCF4, and CYBC1 genes, found on various autosomes. Nevertheless, there are individuals with CGD whose condition cannot be traced to mutations in any of these known genes, indicating unidentified genetic or other factors may be involved in the pathogenesis of their disease.
Chronic granulomatous disease (CGD) follows an X-linked recessive inheritance pattern. The CYBB gene is situated on the X chromosome—one of the two sex chromosomes. In males, possessing just a single altered copy of the CYBB gene on their sole X chromosome is enough to cause the disease. Conversely, females have two X chromosomes, and the condition would only manifest if both copies of the gene carry the mutation, which is a rare occurrence. Hence, X-linked recessive disorders such as CGD are much more common in males. It is also important to note that fathers cannot pass X-linked traits to their sons. On occasion, female carriers of a single mutated copy of the CYBB gene might experience milder symptoms of CGD.
For the CYBA, NCF1, NCF2, or NCF4 gene mutations, CGD is transmitted via an autosomal recessive pattern. This means that the disease only occurs when an individual inherits two mutated genes, one from each parent. The parents, having one mutated gene each, usually do not exhibit any symptoms.
In terms of carrier dynamics, only females can be carriers of the X-linked form of CGD. They are often identified when a male relative is diagnosed with the condition. Female carriers face particular considerations in family planning, as they have a 50% chance of passing the defective gene to their children. Each son born to a carrier has a 50% probability of having CGD, while each daughter has a 50% chance of being a carrier. It is also guaranteed that all daughters of a man with X-linked CGD will be carriers, but none of his sons will inherit the mutated gene, as they will inherit their father’s Y chromosome.
The Nitroblue-tetrazolium (NBT) test has historically been a staple in diagnosing CGD by assessing the ability of neutrophils to produce reactive oxygen species, necessary for combating pathogens. In CGD, the test is negative, indicating a malfunction in these cells.
The Dihydrorhodamine (DHR) 123 test is more sensitive and nowadays more commonly used. It measures the oxidative burst of neutrophils, thereby assessing their ability to respond to infection. This test is particularly useful for monitoring disease progression and guiding treatment, even for asymptomatic carriers.
Molecular genetic testing is critical in identifying specific gene mutations responsible for CGD, which is essential for targeted therapies like gene therapy and decisions regarding bone marrow transplantation. Immunoblot analysis complements this by confirming the absence or malfunction of specific subunits of the NADPH oxidase complex.
For potential parents with a family history of CGD, prenatal testing provides a means to determine if the fetus may be affected by CGD. Analyzing NADPH oxidase activity in fetal neutrophils from blood, amniotic fluid, or chorionic villus sampling can provide an early and reliable diagnosis, informing family planning and early intervention strategies.
The differential diagnosis for chronic granulomatous disease (CGD) is extensive because the symptoms—particularly infections and granulomas—overlap with a variety of other conditions. Conditions such as acne conglobata and acneiform eruptions may mimic the skin manifestations of CGD, while chronic infections and granulomas can be seen in sarcoidosis, fungal infections like coccidioidomycosis, and immunodeficiency states such as common variable immunodeficiency and HIV.
Disorders like allergic bronchopulmonary aspergillosis (ABPA) and cystic fibrosis may present with recurrent pulmonary infections and mimic the lung involvement of CGD. Oral and mucocutaneous lesions can suggest a range of diseases from benign aphthous stomatitis to oral cancers, while gastrointestinal symptoms may overlap with Crohn’s disease or immunodeficiency syndromes.
Hyper-IgE syndrome (Job syndrome) and glutathione synthetase deficiency have immunological and dermatological features that can resemble CGD, necessitating thorough evaluation.
Achieving a precise microbiological diagnosis is crucial for the effective management of infectious diseases. Prophylactic measures using antibacterial and antifungal agents are fundamental in averting infections commonly associated with Chronic Granulomatous Disease (CGD). Treatment typically requires prolonged administration of antimicrobial agents. In the case of abscesses, surgical intervention through percutaneous drainage or surgical removal may be necessary. To mitigate the severe inflammatory reactions, including colitis that can accompany infections, a combined regimen of antimicrobials and corticosteroids may be employed. For ongoing prophylaxis, a daily regimen of trimethoprim-sulfamethoxazole for bacterial prevention and itraconazole for fungal prevention is advised. Additionally, the administration of interferon-gamma three times weekly enhances the immune response and is a standard component of the preventive strategy for CGD.
Hematopoietic stem cell transplantation offers a potential cure and its use is on the rise in treatment protocols.
Gene therapy has seen success in several instances and its application is broadening.
For patients grappling with severe infections, transfusions of granulocytes may be employed as a treatment strategy.
Regular monitoring is advisable: Conducting laboratory tests every three to four months in individuals with CGD who are otherwise healthy can help in the prompt identification and management of infections that have yet to produce symptoms, or those that present with minimal symptoms. This surveillance is also key in detecting and addressing non-infectious complications such as colitis, the formation of granulomas in the lungs, and pulmonary fibrosis.
CGD is predominantly inherited in an X-linked manner with mutations in the CYBB gene, but it can also follow an autosomal recessive pattern when mutations occur in other genes such as CYBA, NCF1, NCF2, NCF4, and CYBC1. When a causative gene mutation is pinpointed within a family, genetic counseling becomes viable. For a mother carrying a CYBB mutation and thus being heterozygous, there is a 50% probability with each pregnancy to pass the mutation on. Sons receiving the mutation will manifest the disease, while daughters will be carriers. Carrier females generally do not exhibit symptoms of CGD but have a significant risk for developing inflammatory disorders. Identification of the CYBB mutation in an affected family member enables the molecular genetic screening of at-risk female relatives.
Individuals with CGD should avoid exposure to decaying organic matter to prevent inhaling potentially harmful fungal spores, which can lead to severe pneumonitis. Live bacterial vaccines, such as BCG and Salmonella typhi, should also be avoided. Furthermore, those with CGD and McLeod neuroacanthocytosis syndrome should not receive blood transfusions containing the Kell antigen.
Screening relatives who may be at risk is crucial for early diagnosis, allowing for the early start of antimicrobial prophylaxis and treatment.
During pregnancy, women with CGD should continue to take prophylactic antimicrobials with caution:
– Trimethoprim is generally avoided due to its antagonistic effect on folic acid, which is critical during pregnancy.
– While sulfamethoxazole has not been shown to increase birth defect risks, it is commonly paired with trimethoprim for non-pregnant prophylaxis.
– The teratogenic potential of itraconazole is unclear, with limited data and inconclusive larger case studies. Due to this uncertainty, some healthcare providers recommend avoiding itraconazole during pregnancy until more definitive information is available.
Patients with Chronic Granulomatous Disease (CGD) who begin showing symptoms after their first year of life typically have a much better long-term prognosis compared to those whose symptoms emerge in infancy. While survival rates have been variable, there has been a notable improvement, with around half of the patients now living into their third or fourth decade. In adults, the frequency of infections may decrease, yet the risk of serious, potentially fatal bacterial infections remains constant across the lifespan.
Fungal infections are a critical factor influencing the life expectancy of individuals with CGD. The disease burden, inclusive of infection-related and granulomatous complications, is especially pronounced in those with the X-linked form of the disease. X-linked CGD often presents more severely, particularly in cases where there is a substantial reduction in residual superoxide production. Despite advances, infections continue to be a leading cause of illness and death in CGD, with the annual mortality rate standing at approximately 1.5% for autosomal recessive CGD and 5% for X-linked CGD.
Prognosis for CGD patients has seen significant enhancements following the introduction of routine prophylactic use of antibiotics, antifungal medications, and interferon-gamma (INF-gamma). It has become increasingly common for patients to live into their thirties and forties.
Individuals with chronic granulomatous disease (CGD) are at heightened risk for invasive infections such as aspergillosis and candidiasis. Sensitization to Aspergillus species can occur in these patients, potentially leading to the development of allergic bronchopulmonary aspergillosis.
Gastrointestinal issues are also common in CGD and may include:
– Inflammation of the intestines, presenting as enteritis and/or colitis
– Conditions similar to Crohn’s disease
– Obstructions at the juncture where the stomach empties into the small intestine
– Persistent inflammation throughout the gastrointestinal tract
The disease can also predispose individuals to rheumatologic conditions such as:
– Discoid lupus erythematosus and systemic lupus erythematosus
– Raynaud’s syndrome, which affects blood flow to extremities
– Nodular vasculitis, involving inflammation of blood vessels
– Juvenile rheumatoid arthritis
– Thrombocytopenia with an immune origin
Other potential complications in CGD include:
– Chorioretinitis, an inflammation that can affect the eyes
– Obstructions within the urinary tract
– Severe recurrent mouth ulcers known as aphthous stomatitis
– Granulomatous cheilitis, causing persistent swelling of the lips