Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells

Blood. 2004 May 1;103(9):3355-61. doi: 10.1182/blood-2003-04-1011. Epub 2004 Feb 5.


Kostmann syndrome, or severe congenital neutropenia (SCN), is an autosomal recessive disorder of neutrophil production. To investigate the potential role of apoptosis in SCN, bone marrow aspirates and biopsies were obtained from 4 patients belonging to the kindred originally described by Kostmann and 1 patient with SCN of unknown inheritance. An elevated degree of apoptosis was observed in the bone marrow of these patients, and a selective decrease in B-cell lymphoma-2 (Bcl-2) expression was seen in myeloid progenitor cells. Furthermore, in vitro apoptosis of bone marrow-derived Kostmann progenitor cells was increased, and mitochondrial release of cytochrome c was detected in CD34(+) and CD33(+) progenitors from patients, but not in controls. Administration of granulocyte colony-stimulating factor (G-CSF) restored Bcl-2 expression and improved survival of myeloid progenitor cells. In addition, cytochrome c release was partially reversed upon incubation of progenitor cells with G-CSF. In sum, these studies establish a role for mitochondria-dependent apoptosis in the pathogenesis of Kostmann syndrome and yield a tentative explanation for the beneficial effect of growth factor administration in these patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis* / drug effects
  • Bone Marrow
  • Case-Control Studies
  • Child, Preschool
  • Cytochromes c / metabolism
  • Family Health
  • Female
  • Granulocyte Colony-Stimulating Factor / administration & dosage
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondria / metabolism
  • Myeloid Progenitor Cells / drug effects
  • Myeloid Progenitor Cells / metabolism
  • Myeloid Progenitor Cells / pathology*
  • Neutropenia / congenital*
  • Neutropenia / drug therapy
  • Neutropenia / etiology*
  • Neutropenia / pathology
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Syndrome


  • Proto-Oncogene Proteins c-bcl-2
  • Granulocyte Colony-Stimulating Factor
  • Cytochromes c