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CHaPtEr 22 Phagocyte Deficiencies 321

affecting isoform A have only SCN, as opposed to patients with
mutations affecting both isoforms (A and B), who develop Primary Autoimmune Neutropenia
neurological problems in addition to SCN. 8 Primary AIN is seen in infancy unassociated with other systemic
Dominant zinc finger mutations disabling transcriptional immune-mediated disorders and is the most common form of
repressor activity of the growth factor independent 1 (GFI1) gene neutropenia, equally affecting boys and girls at around 1/100
4
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have been described in a few patients with SCN. GFI1 is a 000. The average age at diagnosis is 8 months. The majority
transcriptional repressor prooncogene controlling normal present with mild skin and upper respiratory tract infections;
hematopoietic cell differentiation and also regulates ELANE as some patients remain asymptomatic despite low neutrophil
well as several of the CAAT enhancer binding proteins (C/EBP). counts. The majority of patients have a neutrophil count greater
Mutations in GFI1 are also associated with aberrations in than 500 cells/µL at the time of diagnosis, but the ANCs may
lymphoid and myeloid cells, leading to a circulating population transiently increase two- to threefold during severe infection.
of immature myeloid cells. Gfi1 knock-out mice have impaired Bone marrow shows normal to increased cellularity. Myeloid
T-helper type 2 (Th2) regulation and B-cell, Th17, and dendritic- precursors typically reach the myelocyte/metamyelocyte stage.
cell (DC) differentiation. Phagocytosed granulocytes in bone marrow may indicate removal
Mutations in the glucose-6-phosphatase catalytic subunit 3 of sensitized granulocytes there. Granulocyte-specific antibodies
(G6PC3) gene complex cause another form of SCN along with are detected by direct granulocyte immunofluorescence testing
9
developmental and somatic problems. G6PC3 encodes glucose-6- (D-GIFT), the vast majority of which are immunoglobulin G
phosphatase-β, which hydrolyzes glucose-6-phosphate (G6P) in (IgG) against glycoproteins of the granulocyte membrane des-
the final step of gluconeogenesis and glycogenolysis. It is coupled ignated neutrophil antigens (NAs). NAs are located on IgG
to a glucose transporter (G6PT) that facilitates G6P transport receptor IIA or IIIB (FcγRIIa and FcγRIIIb).
from the cytoplasm to the endoplasmic reticulum. Mutations in AIN is generally self-limiting. Disappearance of the antibodies
the G6PT gene lead to glycogen storage disease type Ib, which has from the circulation precedes normalization of neutrophil counts.
variable neutropenia and infections and other complications, such Prophylactic antibiotic treatment should be reserved for those
as liver adenomas, growth retardation, osteoporosis, polycystic with recurrent infections. Alternative treatment strategies for
ovaries, and inflammatory bowel disease (IBD). Children with severe infections and in the setting of emergency surgical interven-
these complications have increased susceptibility to bacterial tions include high-dose intravenous immunoglobulin (IVIG),
infections and cardiovascular abnormalities, including prominent corticosteroids, and G-CSF, with the latter being the most effective
ectatic superficial veins. at increasing the ANC.

Shwachman-Bodian-Diamond Syndrome Secondary Autoimmune Neutropenia
Shwachman-Bodian-Diamond syndrome (SBDS) was first Secondary AIN can be seen at any age and has a more variable
described in 1964 as a disorder with pancreatic exocrine insuf- clinical course. Hepatitis, systemic lupus erythematosus (SLE),
ficiency and bone marrow dysfunction. Currently, it is recognized or Hodgkin disease may underlie it and cause other autoimmune
as the second most common cause of inherited exocrine pancreatic problems as well. These antineutrophil antibodies (ANAs) have
insufficiency after cystic fibrosis. It is autosomal recessive (located pan-FcγRIII specificity. CD18/CD11b antibodies have been
10
at 7q11) with an estimated incidence of 0.5–1/100 000. The SDBS detected in a subset of patients with secondary AIN. This
protein belongs to a highly conserved protein family involved in neutropenia responds poorly to most therapies.
RNA metabolism. Mutations cause defects in the development
of the exocrine pancreas, hematopoiesis, and chondrogenesis. Alloimmune Neonatal Neutropenia
Recurring mutations result from gene conversion caused by First described by Lalezari in 1966, alloimmune neonatal neu-
recombination with a pseudogene in 89% of unrelated patients; tropenia (ANN) is caused by the transplacental transfer of
60% carry two converted alleles. (Pseudogene conversion is also maternal antibodies against the fetal neutrophil antigens NA1,
the cause of the majority of cases of p47 phox -deficient chronic NA2, and NB1, leading to immune destruction of neonatal
13
granulomatous disease [CGD].) neutrophils. These complement-activating antineutrophil IgG
Patients present with recurrent infections, failure to thrive, antibodies can be detected in about 1/500 live births. Antibody
hematopoietic dysfunction, metaphyseal dysostosis, growth coated neutrophils in ANN are phagocytosed by the reticuloen-
retardation, and fatty replacement of the pancreas. Most patients dothelial system and removed from circulation, leaving the
have mild neutropenia, and a few have neutrophil counts below neutropenic neonate at risk for infections. Omphalitis, cellulitis,
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500 cells/µL, which can be intermittent or chronic. Anemia and pneumonia typically occur within the first 2 weeks of life
and thrombocytopenia are associated with neutropenia. Congenital in association with neutropenia. Diagnosis can be made by
aplastic anemia is an unusual presentation. Upper and lower detection of neutrophil-specific alloantibodies in the maternal
respiratory tract pyogenic infections are common and related serum. ANN responds to G-CSF or high-dose IVIG, but most
to neutropenia. Short ribs with broadened anterior ends are patients improve without specific treatment in a few weeks to
common radiological findings, along with metaphyseal dyschon- 6 months with waning of maternal antibody.
droplasia of the femoral head. The diagnosis is suggested by
neutropenia, radiological findings, and abnormal pancreatic DEFECTS OF LEUKOCYTE ADHESION
exocrine function. It is confirmed by gene sequencing.
Migration of circulating leukocytes from the bloodstream into
Autoimmune Neutropenia tissues depends on complex bidirectional interactions between
Autoimmune neutropenia (AIN) is caused by peripheral leukocytes and endothelial cells (Chapter 11). The initial steps
destruction of neutrophils as a result of granulocyte-specific involve the activation of circulating leukocytes by signal molecules
autoantibodies. 12 released from inflamed tissues or from the bacteria themselves.