Clinical characteristics.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder of phagocytes (neutrophils, monocytes, macrophages, and eosinophils) resulting from impaired killing of bacteria and fungi. CGD is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis. Infections typically involve the lung (pneumonia), lymph nodes (lymphadenitis), liver (abscess), bone (osteomyelitis), and skin (abscesses or cellulitis). Granulomas typically involve the genitourinary system (bladder) and gastrointestinal tract (often the pylorus initially, and later the esophagus, jejunum, ileum, cecum, rectum, and perirectal area). Some males with X-linked CGD have McLeod neuroacanthocytosis syndrome as the result of a contiguous gene deletion. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. Use of antimicrobial prophylaxis and therapy has greatly improved overall survival.

Diagnosis/testing.

The diagnosis of CGD is established in a proband with suggestive findings by identification of pathogenic variant(s) in one of six genes that encode or permit assembly of the subunits of phagocyte NADPH oxidase: biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, and NCF4 cause autosomal recessive CGD; pathogenic variants of CYBB cause X-linked CGD.

Management.

Treatment of manifestations: A definitive microbiologic diagnosis is essential to proper treatment of infections. Newer azole drugs (voriconazole, posaconazole, isovuconazole) have expanded therapeutic options for fungal infections. Long courses of antimicrobials are often needed for adequate treatment. Abscesses may require percutaneous drainage or excisional surgery. Simultaneous administration of antimicrobials and corticosteroids can help resolve the associated heightened inflammatory response, including colitis.

Prevention of primary manifestations: Lifelong daily antibacterial and antifungal prophylaxis is recommended; immunomodulatory therapy with interferon gamma (IFN-gamma) is part of the prophylactic regimen in many centers.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known cure for CGD and is associated with excellent overall and event-free survival, especially when performed with matched donors at a younger age.

Surveillance: Screening labs every 3-4 months in a healthy individual with CGD can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and noninfectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis.

Agents/circumstances to avoid: (1) Decayed organic matter (e.g., mulching, gardening, leaf raking, house demolition) as inhalation of fungal spores can result in fulminant pneumonitis; (2) live bacterial vaccines including bacille Calmette-Guérin (BCG) vaccination and Salmonella typhi vaccination; (3) persons with CGD and McLeod neuroacanthocytosis syndrome: blood transfusions that are Kell antigen positive.

Evaluation of relatives at risk: Early diagnosis of relatives at risk allows for prompt initiation of antimicrobial prophylaxis and other treatment.

Pregnancy management: The major concern during the pregnancy of a woman known to have CGD is use of prophylactic antimicrobials: trimethoprim, a folic acid antagonist, is discontinued during pregnancy because of the high risk for birth defects. Although sulfamethoxazole is not known to increase the risk of birth defects in humans, it is typically administered in conjunction with trimethoprim. Data regarding teratogenicity of itraconazole are limited.

Genetic counseling.

CGD associated with a pathogenic variant in CYBB is inherited in an X-linked manner. CGD associated with biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, or NCF4 is inherited in an autosomal recessive manner.

• X-linked CGD. If the mother of an affected male is heterozygous for a CYBB pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygous. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions. Once the CYBB pathogenic variant has been identified in an affected family member, molecular genetic heterozygote detection for at-risk female relatives is possible.
• Autosomal recessive CGD. If both parents are known to be heterozygous for an autosomal recessive CGD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the CGD-causing pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives is possible.

Once the CGD-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. (Other prenatal testing options may be available if the pathogenic variant[s] in the family are not known.)

Suggestive Findings

Chronic granulomatous disease (CGD) should be suspected in individuals (usually children) with the following clinical features, laboratory findings, and family history.

Establishing the Diagnosis

The diagnosis of CGD is established in a proband with suggestive findings by identification of pathogenic (or likely pathogenic) variant(s) in one of six genes that encode or permit assembly of the subunits of phagocyte NADPH oxidase (see Table 1).

• CYBA, CYBC1, NCF1, NCF2, and NCF4 are the genes in which biallelic pathogenic variants cause autosomal recessive chronic granulomatous disease (AR-CGD).
• CYBB is the gene in which a hemizygous or heterozygous pathogenic variant causes X-linked chronic granulomatous disease (X-linked CGD).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings and/or abnormal results on the DHR test are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical findings in whom the diagnosis of CGD has not been considered are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

Chronic granulomatous disease (CGD) is characterized by severe recurrent bacterial and fungal infections and dysregulated inflammatory responses resulting in granuloma formation and other inflammatory disorders such as colitis.

Age at diagnosis. While CGD may present anytime from infancy to late adulthood, the vast majority of affected individuals are diagnosed before age five years. The median age of diagnosis was 2.5 to three years in several series [Jones et al 2008, Martire et al 2008]. More recently, increased numbers of affected individuals have been diagnosed in adolescence or adulthood [Wolach et al 2017, Gao et al 2019, El-Mokhtar et al 2021, Noh et al 2021, Rawat et al 2021]. This delay in diagnosis may be attributed to the following:

• Effective treatment of CGD-related infections with antimicrobials not available in the past
• Recognition of milder cases of autosomal recessive CGD that may have gone undiagnosed without currently available tests and/or awareness of milder disease manifestations
• Overall improvement in food handling and sanitation

Presentation. Infections and granulomatous lesions are usually the first manifestations of CGD, with the most frequent sites being the lung, lymph nodes, liver, bone, and skin. The types of infection seen most often include pneumonia, lymphadenitis, abscess, osteomyelitis, and cellulitis. Other pulmonary complications include empyema and hilar adenopathy. The most common sites for abscesses are the perianal and perirectal areas as well as the liver.

Although the frequency of infections in persons with CGD has decreased with the routine administration of antibacterial and antifungal prophylaxis, infections still occur at a frequency of 0.3/year.

In North America, the majority of infections in CGD are caused by Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species [Marciano et al 2015] (Table 2). In other parts of the world, important causes of infection are Salmonella, bacille Calmette-Guérin (BCG), and tuberculosis [Winkelstein et al 2000, van den Berg et al 2009].

Phenotype Correlations by Gene

CYBB. Historically, it has been recognized that pathogenic variants in CYBB (the cause of X-linked CGD) give rise to a more serious phenotype than pathogenic variants causing autosomal recessive (AR) forms of CGD. Compared to persons with AR-CGD, males with X-linked CGD are typically diagnosed earlier and have a significantly higher incidence of perirectal abscess, suppurative adenitis, gastric outlet obstruction, urinary obstruction, and higher mortality at a young age.

CYBC1 and NCF4 are notable for severe and difficult-to-control inflammatory bowel disease, with relatively less common severe infections.

Genotype-Phenotype Correlations

Hypomorphic (variant) CGD is characterized by partial protein expression/function and residual superoxide production (observed in AR-CGD and protein-positive X-linked CGD). Individuals with hypomorphic variants typically have a milder course and come to clinical attention later in life than those with absent protein expression [Bender et al 2009].

CYBB. Genotype-phenotype correlations in the X-linked gene CYBB (encoding gp91^phox) include the following:

• All nonsense variants or deletions of CYBB in males are highly deleterious and associated with poorer outcomes.
• The phenotype caused by pathogenic variants in CYBB associated with residual superoxide production is characterized by better survival than with CYBB variants that cause no residual superoxide production.
  • Pathogenic missense variants that occur in the CYBB region encoding amino acids 1-309 are associated with residual superoxide production at a level sufficient for good overall survival. Exceptions are pathogenic variants in the nucleotides encoding histidine at residue 222, which do not support production of residual superoxide, and thus are more deleterious.
  • CYBB regions encoding amino acid residues 310 and beyond affect the FAD- and NADPH-binding domains that are essential for superoxide function. Even when pathogenic variants in this region allow protein expression, the proteins are nonfunctional and associated with poorer overall outcomes in affected males [Kuhns et al 2010].

CYBA. Complete CYBA pathogenic variants (defined by the author as those variants resulting in absence of p22^phox protein expression) lead to absent cytochrome b protein expression and thereby disable the formation of the cytochrome complex. These variants therefore behave like the most deleterious of the CYBB pathogenic variants.

No additional specific genotype-phenotype correlations have been identified for CYBC1, NCF1, NCF2, or NCF4.

Nomenclature

When first characterized, chronic granulomatous disease was called "fatal granulomatous disease of childhood" [Bridges et al 1959].

Prevalence

The retrospectively and voluntarily reported prevalence of CGD is approximately 1:200,000 live births in the United States [Winkelstein et al 2000].

Prevalence rates in other countries vary somewhat based on frequency of consanguinity [Wolach et al 2008, Fattahi et al 2011].

In regions with high rates of consanguineous marriages, the prevalence of recessive forms of CGD exceeds that of X-linked CGD.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with chronic granulomatous disease (CGD), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

Antibacterial prophylaxis. No randomized prospective clinical trials of antibacterial prophylaxis in persons with CGD have been performed; however, several retrospective studies suggest that trimethoprim-sulfamethoxazole (TMP-SMX) is effective in preventing bacterial infections. Lifelong daily antibacterial prophylaxis with oral TMP-SMX is recommended at 5 mg/kg up to 320 mg administered in two divided doses. Note: In liquid TMP-SMX the concentration of TMP is 40 mg per 5 mL and sulfamethoxazole 200 mg per 5 mL; the therapeutic dose of TMP-SMX is determined by the TMP component.

Alternatives to TMP-SMX for individuals allergic to sulfonamides include trimethoprim as a single agent, dicloxacillin, cephalosporins, and fluroquinolones.

Antifungal prophylaxis. A randomized prospective blinded crossover trial of itraconazole prophylaxis in persons with CGD showed excellent protection. The use of azole antifungal drugs has markedly reduced the frequency and severity of fungal infections in CGD. Lifelong antifungal prophylaxis with itraconazole 5 mg/kg oral solution to a maximum of 200 mg once daily is recommended [Gallin et al 2003].

For those unable to tolerate itraconazole, posaconazole has been studied in the oncology setting and is likely to be effective in CGD as well [Segal et al 2005].

Of note, the primary prophylaxis used to prevent bacterial and fungal infections also has good activity against yeasts.

Immunomodulatory therapy. A randomized prospective blinded international clinical trial of interferon gamma (IFN-gamma) prophylaxis in persons with CGD showed a 70% reduction in infections in recipients. IFN-gamma has become part of the prophylactic regimen in most centers in the United States; however, opinions differ on its use as primary prophylaxis and in the treatment of acute infections. The exact mechanism of IFN-gamma in CGD is not known, adding to the debate over its utility.

Some practitioners use IFN-gamma only in the setting of acute infection, rather than as primary prophylaxis. The data for this are anecdotal and unimpressive. The authors typically discontinue IFN-gamma during acute infection, as its utility is unclear and the exacerbation of malaise and fever can confuse the clinical picture and alter decision making [Holland 2010].

Administration by injection, cost, and lack of familiarity with cytokine therapy all affect the use of IFN-gamma in CGD. The authors use IFN-gamma in addition to antimicrobials as prophylaxis [Holland 2010]. Dosing is based on body surface area (BSA). For BSA >0.5/m² the dose is 50 μg/m² subcutaneously 3x/week; for BSA ≤0.5/m² the dose is 1.5 μg/kg subcutaneously 3x/week. Fever, myalgias, and malaise are the most common side effects but can be alleviated with concurrent administration of acetaminophen.

Hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT is the only known cure for CGD. Historically, HSCT has been associated with high morbidity and mortality and thus reluctantly offered. However, the use of non-myeloablative conditioning regimens has greatly decreased the risk of regimen-related toxicity as well as allowing for transplantation in the setting of active infection [Güngör et al 2014]. Recent reports show excellent overall survival and event-free survival, especially when HSCT is performed with matched donors and at a younger age [Chiesa et al 2020, Chandra et al 2021].

The issue of which individuals with CGD should undergo HSCT remains complex. While transplant-related mortality rates have fallen dramatically and successful cure has risen, issues of long-term risk, sterility, graft-versus-host disease, donor matching, expense, center experience, availability, and insurance coverage all strongly influence family and physician choices regarding transplantation. Levels of residual superoxide production have correlated well with overall survival [Kuhns et al 2010]; that is, individuals with very low superoxide production had worse long-term survival than those with higher levels of residual superoxide production, suggesting that this latter group could benefit more from transplantation. However, even within this group some individuals do relatively well for long periods.

Individuals with CGD may experience behavioral, emotional, and learning difficulties as a consequence of chronic disease, recurrent hospitalization, and limitations of activity. Older children and adolescents are especially likely to be noncompliant with respect to prophylaxis and risk avoidance, increasing their risk for CGD-related complications. The inflammatory bowel disease present in up to 50% of persons with X-linked CGD may result in discomfort and growth impairment, and may require colostomy or colectomy. Overall quality of life is reduced in children with CGD, whereas those with CGD who have undergone transplant report quality of life comparable to healthy children [Cole et al 2013]. Thus, with improved outcomes HSCT presents an increasingly reasonable alternative and the possibility of a normal life.

As HSCT has become safer, more reliable, and more available it is offered earlier [Chiesa et al 2020] and in some cases is the initial choice for the management of CGD.

The European Bone Marrow Transplantation (EBMT) / European Society of Immunodeficiencies Inborn Errors Working Party [Lankester et al 2021] recommends allogeneic bone marrow transplantation for CGD be considered as soon as possible after diagnosis, prior to onset of disease-related organ damage.

Surveillance

Regular follow-up visits can aid in early detection and treatment of asymptomatic or minimally symptomatic infections and noninfectious complications such as colitis, pulmonary granulomas, and pulmonary fibrosis [Roesler et al 2005].

Agents/Circumstances to Avoid

Exposures. Activities that expose the affected person to decayed organic matter (e.g., mulching, gardening, leaf raking, house demolition) are to be avoided as inhalation of fungal spores can result in fulminant pneumonitis leading to hypoxia and respiratory failure [Siddiqui et al 2007]. Therefore, the following should be avoided:

• Exposure to mulch
• Potting of plants or gardening
• Raking leaves or mowing lawns
• Swimming in stagnant water, brackish water, or ponds

Live bacterial vaccines should be avoided, whereas there is no contraindication to live viral vaccines.

• Bacille Calmette-Guérin (BCG) vaccination should be avoided.
• Salmonella typhi vaccination should be avoided.
• All other vaccines including live viral vaccines are recommended in individuals with CGD.

Transfusion considerations. Persons with CGD and McLeod neuroacanthocytosis syndrome lack red blood cell Kell antigens and thus should not receive blood transfusions that are Kell antigen positive.

Evaluation of Relatives at Risk

For early diagnosis and treatment. It is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of antimicrobial prophylaxis and other treatment. Evaluations include the following:

• Molecular genetic testing if the CGD-related pathogenic variant(s) in the family are known
• Routine dihydrorhodamine (DHR) testing of peripheral blood, which will detect the CGD disease state (except for NCF4-related CGD), if the pathogenic variant(s) in the family are not known

For hematopoietic stem cell donation. Any relative who is a potential hematopoietic stem cell donor should undergo HLA testing to determine if they are a potential match to their relative with CGD. If the relative is a suitable donor, they should undergo DHR testing and/or familial pathogenic variant testing to ensure they are not affected by CGD or heterozygous for X-linked CGD. A heterozygous female relative with a pathogenic variant in CYBB who is a matched donor to a relative with CGD is less acceptable as an HSCT donor compared to an alternative matched related donor or a matched unrelated donor. If there is no other suitable donor, heterozygous females may be considered as donors [Lankester et al 2021].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The major concern during the pregnancy of a woman known to have CGD is continued use of prophylactic antimicrobials:

• Trimethoprim, a folic acid antagonist, is usually avoided in pregnancy.
• Sulfamethoxazole is not known to increase the risk of birth defects in humans; however, it is typically administered in conjunction with trimethoprim for prophylaxis in affected non-pregnant women.
• Data regarding teratogenicity of itraconazole are limited. Although case reports of birth defects in infants born to women taking itraconazole during pregnancy have been published, this observation is not supported by larger case series. Given the lack of adequate data on the use of itraconazole during pregnancy, some practitioners suggest that it should be avoided during pregnancy until such data become available.

The authors' practice for women with CGD who are or are planning to become pregnant is to use antibacterial prophylaxis (e.g., penicillin- or cephalosporin-based therapies) for which more data on safety during pregnancy exist [Author, personal communication]. Although no antifungal prophylactic medications known to be completely safe during pregnancy are currently available, the risks and benefits of antifungal treatment must be weighed case by case. Interferon gamma is held during pregnancy and restarted after breastfeeding has ceased.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Gene therapy. Gene addition therapy using a lentiviral vector to insert a functional copy of CYBB into hematopoietic stem cells is currently under investigation (NCT02234934 and NCT01855685) as a one-time curative therapy for individuals with X-linked CGD [Kohn et al 2020].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Chronic granulomatous disease (CGD) associated with a pathogenic variant in CYBB is inherited in an X-linked manner.

CGD associated with biallelic pathogenic variants in CYBA, CYBC1, NCF1, NCF2, or NCF4 is inherited in an autosomal recessive manner.

Note: The mode of inheritance cannot be confirmed in a family unless the CGD-causing pathogenic variant(s) have been identified in an affected family member. Dihydrorhodamine (DHR) testing can suggest X-linked inheritance or autosomal recessive inheritance, but DHR results are not definitive in establishing a molecular cause or mode of inheritance.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the CYBB pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is presumed to be heterozygous for a CYBB pathogenic variant. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant identified in the proband cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous, the affected male may have a de novo pathogenic variant (in which case the mother is not heterozygous), or the mother may have somatic/germline mosaicism.
• DHR testing of the mother is recommended to confirm her status, assess her risk of inflammatory or infectious conditions (see X-Linked CGD: Heterozygous Females), and facilitate reliable recurrence risk assessment. Genetic testing can also be performed to confirm that the mother is heterozygous for the same CYBB pathogenic variant as the proband.

Parents of a female proband

• A female proband may have the disorder as the result of a de novo pathogenic variant [Gono et al 2008] or a CYBB pathogenic variant inherited from a parent [Lewis et al 2008]. Alternatively, a female proband may have somatic mosaicism for a CYBB pathogenic variant [Wolach et al 2005].
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a CYBB pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically not affected with CGD but are at substantial risk for inflammatory conditions (see X-Linked CGD: Heterozygous Females).
• If the proband represents a simplex case and if the CYBB pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is still greater than that of the general population because of the possibility of maternal germline mosaicism [Gono et al 2008].

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has a CYBB pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
• If the father of the proband has a CYBB pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case and if the CYBB pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is still greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a male proband. Affected males transmit the CYBB pathogenic variant to all of their daughters none of their sons.

Offspring of a female proband. Women with a CYBB pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CYBB pathogenic variant, the parent's family members may be at risk.

Heterozygote detection. Molecular genetic testing of at-risk female relatives requires prior identification of the CYBB pathogenic variant in an affected family member (see Note).

Although females who are heterozygous for X-linked CGD are typically not affected with CGD (see X-Linked CGD: Heterozygous Females), careful longitudinal evaluation of heterozygous females is recommended in order to prevent or treat inflammatory or infectious conditions if they occur, as well as to provide genetic counseling.

Note: Women who are heterozygous for X-linked CGD have circulating populations of oxidase-positive and oxidase-negative phagocytes, which can be resolved by DHR testing if the family-specific pathogenic variant has not been identified. (Note: Nitroblue tetrazolium testing is not reliable for heterozygote detection because it may be falsely interpreted as normal in females who are heterozygous for X-linked CGD).

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive CGD (AR-CGD) are typically heterozygous for a CYBA, CYBC1, NCF1, NCF2, or NCF4 pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CGD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
    Note: Because NCF1 is flanked by two pseudogenes, de novo pathogenic variants can result from gene conversion during meiosis. Such pathogenic variants occur with a low but finite frequency in the general population [Brunson et al 2010] and may explain the rare occurrence of pseudodominant inheritance of CGD caused by NCF1 pathogenic variants.
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an autosomal recessive CGD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with AR-CGD are obligate heterozygotes (carriers) for a pathogenic variant in CYBA, CYBC1, NCF1, NCF2, or NCF4.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for a CYBA, CYBC1, NCF1, NCF2, or NCF4 pathogenic variant, each sib of the proband's parents is at a 50% risk of being a carrier of the familial pathogenic variant.

Carrier detection. Molecular genetic carrier testing for at-risk relatives requires prior identification of the CYBA, CYBC1, NCF1, NCF2, or NCF4 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• Prior to pregnancy, affected women should be advised about changes in antimicrobial prophylaxis (see Pregnancy Management).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the CGD-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing (PGT) are possible.

Percutaneous umbilical blood sampling (PUBS). If the familial pathogenic variant(s) are not known, prenatal diagnosis can be made by analysis of neutrophil oxidase production from umbilical vein samples obtained via PUBS from a fetus at 18-20 weeks gestation. However, this procedure is performed well into the second trimester and is associated with substantial risk [Newburger et al 1979, Ayatollahi & Geramizadeh 2006, Kulkarni et al 2017].

PGT has also been used to identify female HLA-matched sibs of a male with X-linked CGD. After successful in vitro fertilization, embryo transfer, and pregnancy outcome, the female sib served as a hematopoietic stem cell donor for the affected child [Reichenbach et al 2008].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Chronic granulomatous disease is a single phenotype caused by pathogenic variant(s) in of one of six genes that encode proteins of NADPH oxidase. The genes and the official names of their protein products are listed in Table A. However, the protein components are generally known by the names of gp91^phox (encoded by CYBB) and p22^phox (CYBA), which are membrane bound; EROS (CYBC1), which is required for gp91^phox and p22^phox assembly; and p47^phox (NCF1), p67^phox (NCF2), and p40^phox (NCF4), which are cytoplasmic.

Mechanism of disease causation. Pathogenic variants in any one of the six genes that encode the proteins of the NADPH oxidase lead to absent or significantly reduced production of their respective encoded proteins. The reduction in the protein component of the NADPH oxidase causes an inability to produce intracellular reactive oxygen species. This loss in NADPH function allows for select microbes to evade host defense and cause infection.

Gene-specific laboratory technical considerations. The most common NCF1 pathogenic variants deserve special mention as they are due to gene conversions and occur with highly homologous flanking pseudogenes at the NCF1 locus. These are very difficult to discern in exome and genome studies and may require immunoblotting or gene copy number analysis in conjunction with dihydrorhodamine testing for firm diagnosis [Kuhns et al 2019].

Revision History

• 21 April 2022 (ha) Comprehensive update posted live
• 11 February 2016 (ha) Comprehensive update posted live
• 9 August 2012 (me) Review posted live
• 7 November 2011 (jl) Original submission

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