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Congenital neutropenia

Written2002-05Jay L Hess
Department of Pathology, The University of Michigan, M5240 Medical Science I, 1301 Catherine Avenue, Ann Arbor, MI 48109-0602, USA

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Other namesSevere chronic neutropenia (SCN)
Kostmann syndrome
Atlas_Id 10073
Genes implicated inELANE   HAX1  
Note Severe chronic neutropenia is a general term that applies to both congenital and acquired cases. Kostmann syndrome is a subtype of chronic neutropenia with onset in early childhood with an autosomal recessive pattern of development. The term congenital neutropenia is used interchangeably although some authors argue that the term is more appropriate for sporadic cases.


Note Severe chronic neutropenia (SCN) is a heterogeneous group of disorders characterized by chronic neutropenia and serious recurrent infections. The defining characteristic of all of these diseases is the presence of severe neutropenia with absolute neutrophil counts of less than 0.5X109 /L on three separate occasions over a six week period. Some clinically distinctive cases, known as cyclic neutropenia show oscillation in neutrophil levels with a periodicity of approximately 21 days. SCN is distinguished from Shwatchman-Diamond Syndrome by the absence of exocrine pancreas deficiency and growth retardation.
Phenotype and clinics
  • Phenotype stem cell origin: Constitutional disorder affecting myeloid lineage cells
  • Epidemiology: The disease is most common in causcasians and presents in childhood.
  • Clinical features: Congenital neutropenia usually presents in early childhood and is slightly more common in males. Cyclic forms are slightly more common in females.SCN patients develop frequent fevers, skin infections and stomatitis with organisms such as E. coli, S. aureus, and Pseudomonas species. 90% of patients are diagnosed by 6 months of age. Patients tend to develop hematological malignancies (see below)
  • Pathology: The absolute neutrophil count is usually less than 0.2X109 /L. The bone marrow of affected patients shows an arrest in maturation at the promyelocyte stage, often with a monocytosis and sometimes with eosinophilia. The peripheral blood shows a paucity of neutrophils and often monocytosis and eosinophilia.
  • Neoplastic risk Roughly 50% of patients present with myelodysplastic syndromes (MDS), another 10% with therapy associated MDS, 25% with de novo acute myeloid leukemia (AML), and the remainder with a range of other myeloproliferative disorders. The majority of MDS patients transform into AML with a short preleukemic phase.
    Treatment More than 90% of patients respond to G-CSF therapy, which may result in cyclic oscillations in neutrophil count. G-CSF therapy may be complicated by significant bone loss and the development of AML. Hematopoietic stem cell transplantation has shown promise in the treatment of non-responders.
    Prognosis With the advent of G-CSF therapy infectious deaths are rare. Approximately 10% of patients develop AML. This is associated in almost all cases with G-CSF-R mutations. This is not thought to be the direct result of G-CSF therapy but rather an underlying predisposition for the development of myeloid leukemia. Cyclic neutropenia patients do not have an increased risk for development of acute leukemia.


    Inborn conditions The majority of patients have point mutations involving neutrophil elastase located at chromosome 19p13.3.
    Cytogenetics of cancer Cases complicated by the development of AML most commonly show monosomy 7or trisomy 21. Activating RAS mutations are seen in roughly 50% of secondary AML cases.

    Genes involved and Proteins

    Note Most patients show point mutations in ELA2 , a protein that is present in azurophilic granules. In one series of 22 patients 17 different mutations were identified. Most of these were missense mutations. The association between defects in the serine protease ELA2 and neutropenia is thought to involve shortened myeloid progenitor survival. The mechanism of this is obscure. This does not appear to be either loss of function or gain of function (i.e. through cytotoxicity). The evidence to date best supports a dominant negative mechanism whereby the activity of the wild type protein is inhibited. One report suggested that mutation of ELA2 alone was not sufficient for the neutropenia phenotype. It is noteworthy in this regard that mice with knockout of ELA2 show disorders in neutrophil function but not neutropenia.


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    This paper should be referenced as such :
    Hess, JL
    Congenital neutropenia
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(4):307-308.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    External links

    OrphanetAutosomal dominant severe congenital neutropenia
    Other databaseNeutropenia chronic familial (GARD)
    Genes implicated inELANE   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
    Genes implicated inHAX1   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

    REVIEW articlesautomatic search in PubMed
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