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994 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 65: Neutropenia and Neutrophilia 995

Treatment with G-CSF raises blood neutrophil levels, and hematopoi- attributed to a defect in an intracellular transport protein for glucose.
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etic stem cell transplantation corrects the hematologic abnormalities. The marrow appears normal despite severely reduced blood neutrophils.
Without transplantation, the risk of evolution to myelodysplastic syn- The neutrophils have a reduced oxidative burst when stimulated and
drome and acute myelogenous leukemia is 20 percent or greater. 53 defective chemotaxis. 70,71 Treatment with G-CSF is effective for correct-
Diamond-Blackfan Syndrome Neutropenia is a rare complica- ing the neutropenia and improving the associated inflammatory bowel
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tion of hereditary hypoplastic anemia. Other features include congen- disease, but has been associated with evolution to acute myelogenous
ital anomalies of the head and upper limbs. Two genetic loci have been leukemia. 72
identified: 19q13.2 and 8p23. 55,56 The varying severity of neutropenia Cyclic Neutropenia Cyclic neutropenia is an autosomal domi-
may reflect genetic heterogeneity among patients with this diagnosis nant or sporadically occurring disease characterized by regularly recur-
(Chap. 36). ring episodes of severe neutropenia, usually every 21 days. Regular
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Griscelli Syndrome This rare autosomal recessive disorder is oscillations of other white cells, reticulocytes, and platelets are some-
characterized by pigmentary dilution and variable degrees of cellular times observed. Cyclic neutropenia now is attributable to mutations in
immunodeficiency. The syndrome consists of three types. Neutropenia the gene for neutrophil elastase (ELANE) at locus 19q3. Most mutations
is a feature of type 2 but not types 1 or 3. In type 2, the neutropenia in the ELANE gene are in the regions of exons 4 and 5, but there are
is relatively mild and associated with pancytopenia. These hematologic also mutations in exons 2 and 3, as well as in the introns II and IV. 74,23
abnormalities are attributable to a mutation located at 15q21 affecting The diagnosis usually is made in the first year of life, especially in the
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the RAB27a gene. The gene product is a guanosine triphosphatase presence of a family history of the condition. The neutropenic peri-
(GTPase). The mutation also causes abnormal release of granule pro- ods last for 3 to 6 days and often are accompanied by fever, malaise,
teins and hematophagocytosis. As in the Chédiak-Higashi syndrome anorexia, mouth ulcers, and cervical lymphadenopathy. A few cases of
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(Chap. 66), type 2 patients may develop an acute phase of uncontrolled acquired cyclic neutropenia in adults, some of whom have an associated
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lymphocyte and macrophage activation leading rapidly to death. clonal proliferation of large granular lymphocytes (Chap. 94), have been
Hematopoietic stem cell transplantation can correct the hematologic reported. 76
features. Evolution to myelodysplasia has been reported. 60 The diagnosis of cyclic neutropenia can be made only by serial dif-
Chédiak-Higashi Syndrome This rare autosomal recessive disor- ferential white cell counts, at least two or three times per week for a min-
der is characterized by partial oculocutaneous albinism, giant granules imum of 6 weeks. Sequencing of the gene may be helpful in confirming
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in many cells (including granulocytes, monocytes, and lymphocytes), the diagnosis. Most affected children survive to adulthood, with symp-
neutropenia, and recurrent infections (Chap. 66). This syndrome now toms often milder after puberty. Fatal clostridial bacteremia has been
is attributable to a chromosomal mutation at 1q43 affecting the LYST reported in several cases, and careful observation is warranted with
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gene. The product of this gene regulates lysosomal trafficking. In each neutropenic period in untreated patients. Treatment with G-CSF
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Chédiak-Higashi syndrome, the neutropenia usually is mild, and sus- is very effective. G-CSF does not abolish cycling, but it shortens the
ceptibility to infection is attributed to neutropenia and defective micro- neutropenic periods sufficiently to prevent symptoms and infections. In
bicidal activity of the phagocytes. 62 contrast to severe congenital neutropenias, cyclic neutropenia patients
Myelokathexis, WHIM, and Related Syndromes Myelokathe- have no risk to develop leukemias.
xis is a rare autosomal dominant or sporadically occurring disorder Other Inherited Neutropenia Neutropenia caused by genetic
in which patients have severe neutropenia and lymphocytopenia, with defects of folate, cobalamin, and transcobalamin IIA varieties of
total white cell counts often less than 1.0 × 10 /L. WHIM syndrome, congenital disorders lead to disturbed function of methylmalonyl
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characterized by warts, hypogammaglobulinemia, infections, and mye- coenzyme A mutase and methionine synthetase, the two cobalamin-
lokathexis, now is attributable to a mutation in the gene encoding the requiring enzymes. Each of these disorders causes neutropenia,
receptor for the CXC chemokine CXCL12 (previously termed stromal anemia, and thrombocytopenia as a result of ineffective hematopoiesis
cell-derived factor-1), termed CXCR-4. 64,65 The ligand–receptor pair (Chap. 41). 79–81
CXCL-12/CXCR-4 is important for regulating the trafficking of all type Several disorders, currently with only descriptive names, may be
of blood and marrow cells, including hematopoietic stem cells, from genetically determined forms of neutropenia. These cases often are
the marrow to the blood and tissues. In these syndromes, the marrow called familial (benign) neutropenia and probably are autosomal domi-
usually shows abundant precursors and developing neutrophils. Neu- nant disorders. 82–84 Some cases of chronic benign neutropenia of child-
trophils in the marrow and the blood show hypersegmentation with hood (usually a negative family history) may represent new mutations,
pyknotic nuclei and cytoplasmic vacuoles. These morphologic changes and patients with chronic idiopathic neutropenia of adulthood may be
and some molecular studies suggest cell loss in the marrow and blood childhood cases escaping early detection. Until better information is
caused by accelerated apoptosis. Favorable responses to G-CSF and available, these conditions probably are best referred to as “idiopathic
GM-CSF occur, as does evolution to the myelodysplastic syndrome. neutropenias.”
A myelokathexis-like variant of myelodysplastic syndrome has been Acquired Disorders Neutropenia in Neonates of Hypertensive
reported. 66 Mothers Hypertensive women often have low-birth-weight infants
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Cohen Syndrome Cohen syndrome is another rare cause of neu- with low neutrophil counts, attributed to decreased production. The
tropenia. Mental retardation, postnatal microcephaly, facial dysmor- neutropenia often is severe with a high risk of infection, particularly
phism, pigmentary retinopathy, myopia, and intermittent neutropenia during the first few weeks of life. The neutropenia usually resolves
are characteristic features. Patients with Cohen syndrome of diverse within a few weeks. G-CSF elevates the neutrophil count in this form
origins have mutations in the COH1 gene. Current studies suggest that of neonatal neutropenia, but the clinical benefit of treatment remains
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COH1 plays a role in vesicle-mediated sorting and transport of proteins to be determined. 85
within many types of cells. Neutropenia Resulting from Nutritional Deficiencies Neu-
Glycogen Storage Diseases These autosomal recessive disorders tropenia is an early and consistent feature of megaloblastic anemias
are characterized by hypoglycemia, hepatosplenomegaly, seizures, and resulting from vitamin B or folate deficiency. When present it usu-
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failure to thrive in infants. Only type 1b is associated with neutrope- ally is accompanied by macrocytic anemia and mild thrombocytopenia
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nia. The genetic defect in type 1b maps to chromosome 11q23 and is (Chap. 41). Copper deficiency can cause neutropenia in patients on total

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