Congenital neutropenia

2002-05-01   Jay L Hess 

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



Congenital neutropenia


Severe chronic neutropenia (SCN) , Kostmann syndrome


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.


202700 , 610738


C565969 , C567748


486 Autosomal dominant severe congenital neutropenia




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.


    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.


    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 condition

    The majority of patients have point mutations involving neutrophil elastase located at chromosome 19p13.3.

    Cancer cytog

    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


    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.


    Pubmed IDLast YearTitleAuthors
    95852381998Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis.Belaaouaj A et al
    115199782001Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original "Kostmann family" and a review.Carlsson G et al
    110018772000Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.Dale DC et al
    75427471995Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.Dong F et al
    108871022000Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.Freedman MH et al
    117224362001Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia.Germeshausen M et al
    105810301999Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.Horwitz M et al
    112786532001Characterization of mutant neutrophil elastase in severe congenital neutropenia.Li FQ et al
    86243681996Pathophysiology and treatment of severe chronic neutropenia.Welte K et al
    106661902000Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation.Zeidler C et al