Clinical Guidance

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 . CYBB. Genotype-phenotype correlations in the X-linked gene CYBB (encoding gp91phox) include the following:

Source: GeneReviews — "Chronic Granulomatous Disease"

Diagnostic Criteria

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 caused by pathogenic variants in one of six genes that encode or permit assembly of the subunits of phagocyte NADPH oxidase.

Suggestive Findings

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

Clinical features

Source: GeneReviews — "Chronic Granulomatous Disease"

Differential Diagnosis

The differential diagnosis of chronic granulomatous disease (CGD) mainly involves disorders with recurrent or unusual infections or disorders associated with granuloma formation and hyperinflammation (see and ). Note: Spontaneously occurring severe or recurrent bacterial infections should always prompt consideration of immune deficiency. Persons with recurrent soft-tissue infections or staphylococcal lymphadenitis should be evaluated for CGD. Presence of liver abscess or other deep-tissue abscesses is concerning for CGD as well as other immunodeficiencies. Table 3. Disorders of Known Genetic Cause in the Differential Diagnosis of Chronic Granulomatous Disease

Management Guidelines

No clinical practice guidelines for chronic granulomatous disease (CGD) have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with chronic granulomatous disease (CGD), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with Chronic Granulomatous Disease (CGD)

Source: GeneReviews — "Chronic Granulomatous Disease"

Clinical Guidance

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 . 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-Gurin (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.

Source: GeneReviews — "Chronic Granulomatous Disease"

Therapies Under Investigation

Table 8. Chronic Granulomatous Disease: Therapies Under Investigation

Surveillance Guidelines

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 .

Table 7.

Recommended Surveillance for Individuals with Chronic Granulomatous Disease

System/Concern | Evaluation | Frequency in Healthy Person w/CGD No Evidence of Infection or Chronic Inflammatory Symptoms

Early detection of minimally

symptomatic

infections

noninfectious

complications

incl colitis,

pulmonary

granulomata,

pulmonary

fibrosis | • CRP ESR; significant s should prompt eval for infection.

• CBC albumin; presence of microcytic anemia hypoalbuminemia may indicate development of colitis.

• Liver chemistries; transaminase alkaline phosphatase may indicate drug-related hepatotoxicity.

| Every 3-4 mos

Early detection of inflammatory

/or infectious

conditions

in females

heterozygous

for a CYBB

pathogenic

variant | • Annual eval by a health care professional w/an eye toward concerns of invasive infection or for auto-inflammatory manifestations

• To follow (as needed): referral to appropriate specialist lab /or radiologic eval per individual findings

| Annually or if new concern arises

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate

Source: GeneReviews — "Chronic Granulomatous Disease"