CHRONIC GRANULOMATOUS DISEASE - X-LINKED
 
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CHRONIC GRANULOMATOUS DISEASE - X-LINKED

 

DEFINITION:

A disorder of neutrophil function characterized by dysfunctional neutrophils resulting in chronic and recurrent pyogenic and fungal infections of the skin and GI tract and the formation of granulomas and abscesses.

EPIDEMIOLOGY:

  • incidence: CGD most common of the inheritied disorders of neutrophil function (x-linked form represents 50-55% of cases of CGD)
  • age of onset:
    • first 2 years of life
  • risk factors:
    • familial - x-linked recessive
      • chrom.#: Xp21.1
      • gene: cytochrome b - 91 kb subunit

PATHOGENESIS:

1. Background

  • phagocytes lie dormant until activated by a variety of stimuli
  • excite a transmembrane electron transport system -> activiates the NADPH oxidase complex -> catalyzes the respiratory burst -> reduces oxygen to superoxide anion -> superoxide anion dismutated to hydrogen peroxide and hydroxyl radicals by superoxide dismu-tase -> contributes to microbial killing
  • NADPH oxidase complex is composed of:
    • cytochrome b - alpha (22 kb) and beta (91 kb) subunits
    • cytosolic cofactors - 47 kb and 67 kb
  • the reservoir of cytochrome b is found in the specific granules of neutrophils

2. Genetic Defect

  • genetic defect -> absent expression of the beta (91 kb) subunit of cytochrome b -> defective NADPH oxidase complex -> chronic and persistent inflammatory reaction within tissues by seeded microbes -> abscess and granuloma formation in any organ system but particularly the lung, skin, lymph nodes, liver, spleen, and bones
  • because of this defect in the beta subunit, neutrophils

1. cannot generate the superoxide anion

  • determined qualitatively by the reduction of nitroblue tetrazolium (NBT)
  • determined quantitatively by the ferricytochrome reduction method
  • thus, neutrophils are unable to accumulate hydrogen peroxide in the phagosome containing the ingested microorganism and fail to kill them

2. cannot kill catalase-positive microbes

  • catalase-positive microbes use catalase to metabolize hydrogen peroxide but because these defective neutro-phils cannot accumulate hydrogen peroxide, the catalase produced by the microbes is sufficient to protect them from hydrogen peroxide
  • these include:
    • S. aureus
    • gram -: Klebsiella, E. coli, Shigella, Salmonella, Pseudomonas, Aerobacter, Serratia marces-cens
    • fungi : C. albicans, Aspergillus
  • catalase-negative organisms such as Streptococcus and
  • H. flu are killed
  • thus CHD is a disorder of neutrophil function where the neutrophils can ingest but can't kill catalase-positive microorganisms (i.e., reduced intracellular killing)

CLINICAL FEATURES:

1. Early Manifestations

  • chronic and recurrent pyogenic infections during first 2 years of life
  • lymphadenopathy
  • recurrent enlargement of lymph nodes of neck

2. Later Manifestations

1. Gastrointestinal

  • hepatomegaly/hepatosplenomegaly (due to hepatic or peri-hepatic abscesses or granuloma formation)
  • esophageal outlet, pyloric, and/or urethral obstruction (due to granuloma formation)
  • persistent diarrhea - granulomatous colitis
  • perianal abscesses or rectal fistulous tracts

2. Skin

  • eczematoid dermatitis
  • impetigo
  • recurrent skin furunculosis
  • subcutaneous abscesses

3. Other

  • mucous membrane infections
    • conjunctivitis, rhinitis, stomatitis
  • chronic or recurrent pneumonias, CHRONIC GRANULOMATOUS DISEASE - X-LINKED
  • osteomyelitis

3. Female Carriers

  • most are healthy with no history of recurrent infections
  • some have lupus-like skin lesions (photosensitive), pleuritis, and stomatitis

INVESTIGATIONS:

1. CBC

  • 10,000-20,000 WBC's (60-80% PMN's)
  • appropriate neutrophilic leukocytes during infections
  • anemia of chronic disease
  • serum - elevated ZSR
    • normal or elevated immunoglobulins

2. Neutrophil Function

  • chemotaxis - normal
  • superoxide release - decreased
  • bacterial killing - decreased

3. Imaging Studies

1. Chest X-Ray

  • abnormal in 90% of cases

2. Scans

  • of all organ systems for abscesses, osteomyelitis

4. Diagnosis

1. For Superoxide Anion Deficiency

1. Qualitative

  • reduced reduction of NBT (neutrophil membrane remains yellow after exposure to NBT; it would normally turn purple if the anion was produced)

2. Quantitative

  • abnormal ferricytochrome reduction test

2. Prenatal

  • NBT slide test on cord or placental blood
  • RFLP with X-CGD gene-linked probes

MANAGEMENT:

1. Infections

1. Acute

  • IV antibiotics
  • corticosteroids
    • may help to resolve granulomas
  • granulocyte transfusions
    • short term (1 wk) transfusions may help for infections unresponsive to IV antibiotics
  • gamma interferon
    • may increase the generation of superoxide anion by
    • 1-10%
    • may decrease the number of new infections and improve the response to existing infections

2. Prophylaxis

1. TMP-SMZ

  • increases duration of infection-free periods
  • benefit if instituted before the formation of chronic foci of infection

2. Complications

1. Gastric Outlet Obstruction and Granulomatous Colitis

  • prolonged antimicrobial therapy and prednisone

3. Bone Marrow Transplantation

  • has met with limited success

INTERNET LINKS:

The Chronic Granulomatous Disease Association
 Chronic Granulomatous Disease (CGD)

 

 

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