Severe Congenital Neutropenia

doi:10.1053/j.seminhematol.2006.04.004

Seminars in Hematology

Volume 43, Issue 3, July 2006, Pages 189-195

https://doi.org/10.1053/j.seminhematol.2006.04.004 Get rights and content

Severe congenital neutropenia (CN) includes a variety of hematologic disorders characterized by severe neutropenia, with absolute neutrophil counts (ANC) below 0.5 × 10⁹/L, and associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive disorder, characterized histopathologically by early-stage maturation arrest of myeloid differentiation. CN with similar clinical features occurs as an autosomal dominant disorder and many sporadic cases also have been reported. This genetic heterogeneity suggests that several pathophysiological mechanisms may lead to this common clinical phenotype. Recent studies on the genetic bases of CN have detected inherited or spontaneous point mutations in the neutrophil elastase gene (ELA 2) in about 60% to 80% of patients and, less commonly, mutations in other genes. Acquisition of additional genetic defects during the course of the disease, for example, granulocyte colony-stimulating factor (G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability as a common feature for all congenital neutropenia subtypes. Data on more than 600 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that, regardless of the particular CN subtype, more than 95% of these patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 × 10⁹/L. Adverse events include mild splenomegaly, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment impacts on these adverse events is not fully understood. In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC >1,000/μL) in the risk of developing acute myeloid leukemia (AML) has been reported. Hematopoietic stem cell transplantation (HSCT) is still the only treatment available for patients who are refractory to G-CSF treatment.

Section snippets

Pathophysiologic Mechanisms

The underlying genetic defect of CN is still only partially understood. The original hypotheses for this disorder included defective production of G-CSF or defective response of the neutrophilic precursors to G-CSF or other hematopoietic growth factors. We showed, however, that serum from patients with CN contains normal or increased levels of G-CSF¹² with normal biological activity of endogenous G-CSF and that G-CSF receptors are expressed on myeloid cells from CN patients in normal or

Diagnosis

CN is a rare condition with an estimated frequency of approximately one to two cases per million with equal distribution for gender. The disease is usually detected in infancy after fever or signs of a severe infection develop. CN patients suffer from severe chronic neutropenia with ANCs continuously below 200/μL; in many cases, peripheral blood neutrophils are completely absent. With infection, there may be a transient increase in neutrophils, but counts rarely increase to normal levels. The

Treatment

rHuG-CSF has been available for treatment of CN since 1987. Phase I–III studies have demonstrated its efficiency in increasing the number of neutrophils associated with reduction of infections.6, 32 In contrast, GM-CSF treatment does not lead to an increase in blood neutrophils but only in blood eosinophils.³³

In 1994, the SCNIR was established to collect data on clinical course and outcome of these rare disorders. As of December 2005, 611 patients with CN have been registered, and more than 95%

Long-Term Safety

Prior to the development and availability of G-CSF, complications of severe congenital neutropenia were not well known. There was no organized database for this rare disease. However, a number of reports noting deaths from infections and a few cases evolving to AML are available from the pre–G-CSF era.

Monitoring

The Advisory Board for the SCNIR recommends that all patients should be seen by a physician at least twice per year with assessment for weight and height and documentation of the occurrence of infections. Blood counts (white blood cells, hemoglobin, platelets, and differential blood counts) should be obtained at least every 3 months. Bone marrow examination (morphology plus cytogenetics) is required once per year to search for acquired cytogenetic abnormalities, such as monosomy 7 or trisomy

Conclusion

In light of the current literature and longitudinal data from the SCNIR, we suggest that the use of rHuG-CSF remain first-line treatment for most CN patients. HSCT from an HLA-identical sibling is beneficial for patients who are refractory to rHuG-CSF. For those patients in whom a G-CSF receptor mutation is identified, HSCT from an HLA-identical sibling is an option. Patients who develop monosomy 7, other significant chromosomal abnormalities, or MDS/leukemia should proceed urgently to HSCT.

Acknowledgment

The authors thank all colleagues associated with the Data Collection Centers of the Severe Chronic Neutropenia International Registry at the University of Washington, Seattle, WA (Audrey Anna Bolyard and Tammy Cottle), and the Medizinische Hochschule, Hannover, Germany (Beate Schwinzer and Gusal Pracht) for their continued assistance. We are also grateful to the many physicians worldwide who faithfully and generously submitted data on their patients. The authors gratefully acknowledge the

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Severe Congenital Neutropenia

Section snippets

Pathophysiologic Mechanisms

Diagnosis

Treatment

Long-Term Safety

Monitoring

Conclusion

Acknowledgment

Am J Med

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

J Pediatr

J Pediatr

Infantile genetic agranulocytosis

Acta Pediatr Scand

Infantile genetic agranulocytosisA review with presentation of ten new cases

Acta Pediatr Scand

Recombinant human granulocyte colony-stimulating factorEffects on normal and leukemic myeloid cells

Science

Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis

N Engl J Med