Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

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

(Note : for Links provided by Atlas : click)


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.


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.

    Genes involved and Proteins


    Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis.
    Belaaouaj A, McCarthy R, Baumann M, Gao Z, Ley TJ, Abraham SN, Shapiro SD
    Nature medicine. 1998 ; 4 (5) : 615-618.
    PMID 9585238
    Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original Kostmann family and a review.
    Carlsson G, Fasth A
    Acta paediatrica (Oslo, Norway : 1992). 2001 ; 90 (7) : 757-764.
    PMID 11519978
    Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.
    Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, Boxer LA, Kannourakis G, Zeidler C, Welte K, Benson KF, Horwitz M
    Blood. 2000 ; 96 (7) : 2317-2322.
    PMID 11001877
    Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.
    Dong F, Brynes RK, Tidow N, Welte K, Löwenberg B, Touw IP
    The New England journal of medicine. 1995 ; 333 (8) : 487-493.
    PMID 7542747
    Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.
    Freedman MH, Bonilla MA, Fier C, Bolyard AA, Scarlata D, Boxer LA, Brown S, Cham B, Kannourakis G, Kinsey SE, Mori PG, Cottle T, Welte K, Dale DC
    Blood. 2000 ; 96 (2) : 429-436.
    PMID 10887102
    Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia.
    Germeshausen M, Schulze H, Ballmaier M, Zeidler C, Welte K
    British journal of haematology. 2001 ; 115 (1) : 222-224.
    PMID 11722436
    Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.
    Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC
    Nature genetics. 1999 ; 23 (4) : 433-436.
    PMID 10581030
    Characterization of mutant neutrophil elastase in severe congenital neutropenia.
    Li FQ, Horwitz M
    The Journal of biological chemistry. 2001 ; 276 (17) : 14230-14241.
    PMID 11278653
    Pathophysiology and treatment of severe chronic neutropenia.
    Welte K, Dale D
    Annals of hematology. 1996 ; 72 (4) : 158-165.
    PMID 8624368
    Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation.
    Zeidler C, Welte K, Barak Y, Barriga F, Bolyard AA, Boxer L, Cornu G, Cowan MJ, Dale DC, Flood T, Freedman M, Gadner H, Mandel H, O'Reilly RJ, Ramenghi U, Reiter A, Skinner R, Vermylen C, Levine JE
    Blood. 2000 ; 95 (4) : 1195-1198.
    PMID 10666190


    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
    Last year articlesautomatic search in PubMed

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Wed Jul 28 17:43:15 CEST 2021

    Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us