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Volume 27, Issue 1, Pages 1-156 (February 2013)
NeutropeniaEdited by Christoph Klein
| Epidemiology of Congenital NeutropeniaReview ArticlePages 1-17 Jean Donadieu, Blandine Beaupain, Nizar Mahlaoui, Christine Bellanné-Chantelot | |||||
Epidemiologic
investigations of congenital neutropenia aim to determine several
important indicators related to the disease, such as incidence at birth,
prevalence, and outcome in the population, including the rate of severe
infections, leukemia, and survival. Genetic diagnosis is an important
criterion for classifying patients and reliably determining the
epidemiologic indicators. Patient registries were developed in the
1990s. The prevalence today is probably more than 10 cases per million
inhabitants. The rate of infection and leukemia risk can now be
calculated. Risk factors for leukemia seem to depend on both the genetic
background and cumulative dose of granulocyte colony stimulating
factor.
| ELANE Mutations in Cyclic and Severe Congenital Neutropenia: Genetics and PathophysiologyReview ArticlePages 19-41 Marshall S. Horwitz, Seth J. Corey, H. Leighton Grimes, Timothy Tidwell | |||||
The
2 main forms of hereditary neutropenia are cyclic (CN) and severe
congenital (SCN) neutropenia. CN is an autosomal dominant disorder in
which neutrophil counts fluctuate with 21-day periodicity. SCN consists
of static neutropenia, with promyelocytic maturation arrest in the bone
marrow. Unlike CN, SCN displays frequent acquisition of somatic
mutations in the gene CSF3R. CN is caused by heterozygous mutations in the gene ELANE, encoding neutrophil elastase. SCN is genetically heterogeneous but is most frequently associated with ELANE
mutations. We discuss how the mutations provide clues into the
pathogenesis of neutropenia and describe current hypotheses for its
molecular mechanisms.
| Genetics and Pathophysiology of Severe Congenital Neutropenia Syndromes Unrelated to Neutrophil ElastaseReview ArticlePages 43-60 Kaan Boztug, Christoph Klein | |||||
Considerable
progress has been made in recent years in understanding of the genetic
basis for congenital neutropenia syndromes. With the advent of
high-throughput genomic analyzing technologies, the underlying genetic
causes of other congenital neutropenia syndromes are expected to be
resolved in the near future. This knowledge will provide the foundation
for genotype-phenotype correlations for infection susceptibility,
response to therapy, and risk of malignant transformation, enabling
optimal care for individual patients depending on their molecular
pathophysiology. It is hoped that these investigations will enable the
development of tailored molecular therapies to specifically correct the
aberrant signaling cascades.
| Granulocyte Colony-Stimulating Factor Receptor Signaling: Implications for G-CSF Responses and Leukemic Progression in Severe Congenital NeutropeniaReview ArticlePages 61-73 Ivo P. Touw, Karishma Palande, Renée Beekman | |||||
Following
activation by their cognate ligands, cytokine receptors undergo
intracellular routing toward lysosomes, where they are degraded. This
review focuses on the signaling function of the G-CSFR in relation to
the dynamics of endosomal routing of the G-CSFR. Mechanisms involving
receptor lysine ubiquitination and redox-controlled phosphatase
activities are discussed. Specific attention is paid to the consequences
of G-CSFR mutations, acquired in patients with severe congenital
neutropenias who receive G-CSF therapy, particularly in the context of
leukemic transformation, a major clinical complication of the disease.
| Defective G-CSFR Signaling Pathways in Congenital NeutropeniaReview ArticlePages 75-88 Julia Skokowa, Karl Welte | |||||
Several
signaling systems downstream of G-CSFR have been identified that are
defective or hyperactivated in myeloid cells of patients with congenital
neutropenia: severely reduced expression of myeloid-specific
transcription factors LEF-1 and C/EBPα, severely reduced expression and
functions of HCLS1 protein, severely reduced expression of neutrophil
elastase protein, dramatic compensatory up-regulation of the NAMPT/NAD+/SIRT
pathway leading to continuous activation of emergency granulopoiesis
via the transcription factor C/EBPβ, and hyperactivation of STAT5
protein by tyrosine phosphorylation.
| Chronic Granulomatous DiseaseReview ArticlePages 89-99 Steven M. Holland | |||||
Chronic
granulomatous disease (CGD) is a paradigm for nonlymphoid primary
immune defects, and has guided elucidation of oxygen metabolism in the
phagocyte, vasculature, and brain. It has been in the forefront of the
development of antimicrobial prophylaxis before the advent of advanced
HIV and before its routine use in neutropenia. It has been an attractive
target for gene therapy and bone marrow transplantation for
nonmalignant diseases. Therefore, CGD is worthy of attention for its
historical interest and because it is a disease for which expert
management is imperative.
| Leukocyte Adhesion DeficienciesReview ArticlePages 101-116 Edith van de Vijver, Timo K. van den Berg, Taco W. Kuijpers | |||||
During
inflammation, leukocytes play a key role in maintaining tissue
homeostasis through elimination of pathogens and removal of damaged
tissue. Leukocytes migrate to the site of inflammation by crawling over
and through the blood vessel wall, into the tissue. Leukocyte adhesion
deficiencies (ie, LAD-I, -II, and LAD-I/variant, the latter also known
as LAD-III) are caused by defects in the adhesion of leukocytes to the
vessel wall, resulting in severe recurrent nonpussing infections and
neutrophilia, often preceded by delayed separation of the umbilical
cord. Although dependent on the genetic defect, hematopoietic stem cell
transplantation is often the only curative treatment.
| Clinical and Molecular Pathophysiology of Shwachman–Diamond Syndrome: An UpdateReview ArticlePages 117-128 Kasiani C. Myers, Stella M. Davies, Akiko Shimamura | |||||
Shwachman–Diamond
syndrome (SDS) is an inherited neutropenia syndrome associated with a
significant risk of aplastic anemia and malignant transformation.
Multiple additional organ systems, including the pancreas, liver, and
skeletal and central nervous systems, are affected. Mutations in the
Shwachman-Bodian-Diamond syndrome (SBDS) gene are present in most
patients. There is growing evidence that SBDS functions in ribosomal
biogenesis and other cellular processes. This article summarizes the
clinical phenotype of SDS, diagnostic and treatment approaches, and
novel advances in our understanding of the molecular pathophysiology of
this disease.
| Animal Models of Human Granulocyte DiseasesReview ArticlePages 129-148 Alejandro A. Schäffer, Christoph Klein | |||||
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