Page 809 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 50 Disorders of Phagocyte Function 695

TABLE Classification of Chronic Granulomatous Disease
50.1
Flavocytochrome Defect in
−
Component Gene NBT Score (% O 2 Production (% b Spectrum (% Cell-Free NADPH Frequency
Affected Symbol Gene Locus Inheritance Subtype a Positive) Normal) Normal) Oxidase Assay (% of Cases) b
Gp91 phox CYBB Xp21.1 X X91° 0 0 0 Membrane 68
X91 − 80−100 (weak) 3−30 Low Membrane 5
X91 − 5−10 5−10 Low Membrane <1
X91 + 0 0 N Membrane 1
P22 phox CYBA 16p24.3 AR A22° 0 0 0 Membrane 4
A22 + 0 0 N Membrane <1
P47 phox NCF1 7q11.23 AR A47° 0 0−1 N Cytosol 17
P67 phox NCF2 1q25.3 AR A67° 0 0 N Cytosol 5
p40 phoxc NCF4 22q13.1 AR A40 + 100 <10 (intracellular) N n/a 1
a In this nomenclature, the first letter represents the mode of inheritance (X-linked [X] or autosomal recessive [A]), and the number indicates the phox component that is
genetically affected. The superscript symbols indicate whether the level of protein of the affected component is undetectable (°), diminished (−), or normal (+) as
measured by immunoblot analysis.
b Combined data from 209 kindreds evaluated at the Scripps Research Institute/Stanford University CGD Clinic and a cooperative European study representing 57
kindreds and 63 patients. (Courtesy Casimir C, Chetty M, Bohler MC, et al: Identification of the defective NADPH-oxidase component in chronic granulomatous disease:
A study of 57 European families. Eur J Clin Invest 22:403, 1992; and Curnutte JT: Chronic granulomatous disease: The solving of a clinical riddle at the molecular level.
Clin Immunol Immunopathol 67:S2, 1993.) These frequencies remain similar to those in more recent reports from Europe and the United States.
c A single patient reported to date who was a compound heterozygote for a frameshift mutation and a nonfunctional form of p40 phox caused by a point mutation. (Matute
JD, Arias AA, Wright NA et al: A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in
neutrophil NADPH oxidase activity. Blood 114:3309, 2009.)
AR, Autosomal recessive inheritance; N, normal; NADPH, nicotinamide adenine dinucleotide phosphate; n/a, not applicable; NBT, nitroblue tetrazolium; X, X-linked
inheritance.

3,8
Summary of Mutations in the CYBB Gene Encoding rheumatologic complications. Because of this heterogeneity, the
TABLE gp91 pbox in 261 Kindreds With X-linked Chronic diagnosis of CGD should be entertained, not only in young children
50.2 with recurrent severe infections, but also in adolescents and young
Granulomatous Disease
adults who experience exceptionally severe or unusual infections.
Number of Frequency
Type of Mutation Kindreds (%) Phenotype
Clinical Manifestations
Deletions 63 24.2 X91°
Insertions 27 10.3 X91°
In approximately two-thirds of patients, the first symptoms of CGD
Splice-site mutations 42 16.1 X91° appear during the first year of life with the onset of recurrent, purulent
7
Missense mutations 59 22.6 X91°, X91−, X91+ bacterial, and fungal infections. Table 50.3 summarizes the types of
infections and infecting organisms most frequently encountered in
Nonsense mutations 70 26.8 X91° CGD. The most common types of infections are those that involve
Data from Roos D, Curnutte J, Hossle JP, et al: X-CGDbase: A database of sites in contact with the outside world, which is consistent with the
X-CGD-causing mutations. Immunol Today 17:517, 1996.
role of neutrophils as a first line of defense against infection. Staphy-
lococcus aureus, enteric gram negatives, Serratia marcescens, B. cepacia,
Nocardia spp., and Aspergillus spp. represent the most frequently
encountered pathogens in North American patients, but Burkholderia
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Even though more than 90% of patients with CGD have respira- and Nocardia spp. are less frequently seen in Europe. S. aureus is the
−
tory burst defects that result in undetectable levels of O 2 production, most frequently isolated organism overall. The most common causes
there is a surprising heterogeneity in the clinical manifestations of the of death have been pneumonia or sepsis caused by B. cepacia and
7
disease. At one end of the spectrum are patients who begin to have Aspergillus spp., although use of newer azole antifungals has markedly
severe bacterial and fungal infections during infancy and who rarely improved the outcome of the latter in recent years. 7,8
have more than 4 to 12 months between such serious infections. At Most CGD pathogens share the property of being catalase nega-
the other end of the spectrum are patients who are well for many tive, and as such inadvertently “lend” H 2 O 2 secreted from the
years and then unexpectedly develop a serious infection typical of pathogen to the peroxide-starved CGD phagocyte, which in turn uses
CGD, such as a staphylococcal hepatic abscess or Aspergillus pneu- it (after being converted to hypochlorous acid [HOCl] by MPO; see
monia. After their first major infection, some of these patients may Fig. 50.3) to kill the microbe. It also appears that at least some of the
be relatively healthy again for another 3 to 10 years before the next CGD pathogens are resistant to the nonoxidative killing mechanisms
severe infection occurs. As a group, patients with X-CGD, A22 of the phagocyte. It is somewhat surprising how often one fails to
CGD, and A67 CGD seem to have a more severe clinical course identify the infecting organism in CGD—perhaps greater than half
7,9
compared with patients with A47 CGD, who have a small amount the time despite aggressive culturing. In this situation, one treats
of detectable oxidant production even in the complete absence of this empirically with the antibiotic that should work and if it fails, one
subunit (Fig. 50.5G). Individuals with partial respiratory burst activ- then aggressively pursues more invasive diagnostic procedures looking
ity but less than 10% of normal (most X91− patients; see Table 50.1) for one (or more) of the less commonly seen microbes such as
also tend to have disease of intermediate severity. Polymorphisms in Nocardia spp., Candida spp., mycobacteria, and a host of other
oxygen-independent antimicrobial systems or other components bacteria and fungi (see Table 50.3). Other unusual organisms that
regulating the innate immune response are also likely to play an cause infection in CGD include other members of the Burkholderia
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important role in modifying disease severity. Specific polymorphisms family, including Burkholderia cenocepacia, Burkholderia gladioli, and
in the MPO, mannose binding lectin, and FcγRIIa genes are associ- Burkholderia mallei (the causative agent in melioidosis, a septic illness
ated with a higher risk for granulomatous or autoimmune or common in East Asia), and Chromobacterium violaceum, found in