Page 808 - Hematology_ Basic Principles and Practice ( PDFDrive )

694 Part VI Non-Malignant Leukocytes

CYBB Clinical Approach to Patients With Disorders of Phagocyte Function
– ~65%
O 2 O 2 (X-linked) Flavocytochrome b 558
Index of Suspicion
Patients with disorders of phagocyte function usually present at a
CYB young age with recurrent, deep-seated bacterial and fungal infections.
e– gp91 phox p22 phox A Unlike patients with severe neutropenia caused by bone marrow (BM)
Membrane (Nox2) ~5% failure, these patients usually do not have sepsis. Blood cultures are
often negative. The major diagnostic problem faced by the clinician is
Cytosol to determine if the history of infection is unusual enough to warrant
consideration of an underlying neutrophil dysfunction defect. The first
NADPH NCF1 point to remember is that primary immunodeficiency disorders are
~25% rare and primary neutrophil dysfunction syndromes form only a small
NADP + percentage of all primary immunodeficiency syndromes. The patient
is more likely to have recurrent community-acquired Staphylococcus
Rac p67 phox p47 phox infection than CGD.
Specific features that may suggest a phagocytic defect are shown in
NCF2 phox NCF4 Fig. 50.2. Excellent discussions of this problem have been published
~5% p40 1 patient (see Kyono and Coates , and Dinauer, Newburger and Borregaard ).
2
3
Four aspects of each patient’s infection history should be considered:
Fig. 50.4 NICOTINAMIDE ADENINE DINUCLEOTIDE PHOS- frequency, severity, location, and responsible pathogen. Patients with
PHATE OXIDASE AND MOLECULAR GENETICS OF CHRONIC unusual features in at least one of these aspects should alert the clini-
GRANULOMATOUS DISEASE. Shown are the membrane and soluble cian to a possible underlying phagocyte disorder. When considering
subunits of NADPH oxidase, indicating how these correspond to the five frequency, the patient’s age and associated medical conditions must
different genetic subgroups of chronic granulomatous disease (CGD) and be taken into account. For example, recurrent otitis media in a 2-year-
old patient is far less worrisome than a similar history in a 40-year-old
their approximate incidence. Flavocytochrome b 558 is the redox center of the patient. The more unusual or severe the infections, the less frequently
enzyme and is located in plasma, specific granule, and phagolysosomal mem- these have to occur before a phagocyte evaluation is indicated. Infec-
branes. This heterodimer is composed of the gp91 phox and p22 phox subunits tions in unexpected anatomic locations, such as hepatic, pulmonary,
of the NADPH oxidase, which are affected in X-linked and an autosomal and rectal abscesses, may indicate an underlying phagocyte defect.
recessive (AR) form of CGD, respectively. The soluble regulatory proteins Childhood periodontal disease or gingivitis is distinctly uncommon, and
p47 phox , p67 phox , and p40 phox are found in the cytosol until phagocyte activation in the absence of neutropenic conditions, strongly suggests underlying
by soluble or particulate inflammatory stimuli, after which they move to neutrophil dysfunction. The identification of certain pathogens (e.g.,
the membrane where p47 phox and p67 phox bind flavocytochrome b558, binds Serratia marcescens, Klebsiella spp., Aspergillus spp., Nocardia spp.,
Rac, and p40 phox binds phosphatidylinositol 3-phosphate, a phosphoinositide Burkholderia cepacia, invasive candidiasis) in children and young adults
can provide the strongest indications for pursuing further studies. A
present on phagosome membranes. Mutations in the genes encoding p47 phox , history of delayed separation of the umbilical cord is often mentioned
p67 phox and p40 phox account for other AR forms of CGD. Another essential as a sign of phagocytic defect. This is fairly common as an isolated
regulatory component of the NADPH oxidase is the small GTPase, Rac, finding and is usually of no significance. However, this in conjunction
which in its active guanosine triphosphate-bound state, becomes membrane with omphalitis or other pyogenic infections raises the possibility of
bound, and associates with the oxidase. By a mechanism that is not fully leukocyte adhesion deficiency (LAD) or chemotactic defects. A child
understood, binding of these multiple regulatory subunits activates the with nystagmus, fair skin, and recurrent staphylococcal infections
flavocytochrome to catalyze the transfer of electrons from cytosolic NADPH should be evaluated for Chediak-Higashi syndrome (CHS).
across the membrane via the FAD and heme redox centers to molecular Evaluation
oxygen, thereby forming superoxide in the extracellular or intraphagosomal Performing a good history and physical examination to eliminate
compartment. No cases of CGD have been described owing to mutations common causes of recurrent infection is important before looking for
in Rac. FAD, Flavin adenine dinucleotide; NADPH, nicotinamide adenine rare syndromes. For example, is the recurrent pneumonia caused by
dinucleotide phosphate an aspirated foreign body in the bronchus? In general, patients should
first be evaluated for lymphocyte or complement defects. A useful
algorithm is presented in Fig. 50.2. Note that testing described in this
algorithm is not exhaustive, and patients with truly striking histories of
unusual kinds of infections should be referred for further evaluation by
phox
AR CGD involving p22 (MIM 233690) occurs in approxi- specialized research laboratories.
mately 5% of CGD patients and usually involves the complete
absence of cytochrome b (A22°), encoded by CYBA. Mutations in
A22 CGD are heterogeneous and range from large interstitial gene
deletions to point mutations associated with missense, frameshift, or
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RNA splicing defects. Because the full expression of flavocytochrome deletion. This close physical proximity leads to recombination events
b in the membrane requires the production of both subunits, a between the wild-type gene and pseudogene(s).
primary deficiency of either component leads to a secondary loss of A heterogeneous group of mutations in the p67 phox gene, NCF2,
the other. Thus, neither subunit can be detected on immunoblot are responsible for A67 CGD, a rare AR form of CGD (MIM233710)
+
12
analysis in either X91° or A22° CGD. A single patient with A22 accounting for about 5% of cases overall. Almost all mutations
CGD has been described with a missense mutation disrupting the identified to date in A67 CGD lead to absent expression of the p67 phox
+
binding site for p47 phox . protein. However, one A67 patient has been reported in which a
AR patients with p47 phox -deficient CGD (MIM 233700) account nonfunctional form of p67 phox with an amino acid deletion is expressed
for approximately one-fourth of cases in the United States and but is unable to translocate to the membrane or bind to Rac.
Europe, but only about 7% of cases in Japan. The p47 phox subunit is Finally, a boy with AR p40 phox defects (MIM613960) was recently
10
encoded by the NCF1 gene. A limited number of mutations have reported. This patient was a compound heterozygote for two null
12
been identified in NCF1. Virtually all patients are either homozy- alleles in NCF4. Although NADPH oxidase activity on the plasma
gotes or compound heterozygotes for a mutant allele with a GT membrane was normal, phagosome oxidant production was mark-
deletion at the beginning of exon 2 that predicts a premature stop edly impaired. The main clinical manifestation in this patient was
codon following the amino acid residue and results in absence of the chronic granulomatous inflammation of the intestinal tract rather
p47 phox protein. The high frequency of the p47 phox GT deletion muta- than opportunistic infections characteristic of CGD, perhaps related
tion appears to reflect the existence of at least one closely linked to the more selective role of p40 phox in regulating NADPH oxidase
highly conserved p47 phox pseudogene(s) that contains this GT activity.