A comparison of the defective granulopoiesis in childhood cyclic neutropenia and in severe congenital neutropenia.
OBJECTIVE
Cyclic neutropenia (CyN) in childhood and severe congenital neutropenia (SCN) are congenital disorders that cause chronic neutropenia. Mutations in the neutrophil elastase gene, ELA2, have been reported in patients with CyN and in those with SCN. We examined granulopoietic defects in CyN patients with those in SCN patients.


METHODS
Three patients with CyN and four with SCN were enrolled in this study. Bone marrow cells were enriched based on the expression of CD34, Kit, and granulocyte colony-stimulating factor receptor (G-CSFR). The purified cells were assayed for colony formation, proliferation, and mRNA expression of granular enzymes.


RESULTS
All patients showed heterozygous mutations of ELA2. Flow cytometric analysis demonstrated no differences in the frequency of CD34, Kit, and G-CSFR expression between CyN patients and normal subjects. Significant differences in granulocyte/macrophage (GM)-colony formation of CD34(+)/Kit(+) cells were observed among CyN patients, SCN patients, and normal subjects in response to hematopoietic factors. Impaired granulopoiesis was found in both CD34(+)/Kit(+)/G-CSFR(+) and CD34(+)/Kit(+)/G-CSFR- cells in patients with CyN, whereas this impairment was observed only in CD34(+)/Kit(+)/G-CSFR(+) cells in SCN patients, as previously reported. The mRNA expression of granular enzymes in myeloid precursors and the transcription levels during myeloid cell differentiation in CyN patients were comparable to those in normal subjects, in contrast to the abnormal transcription of granular enzymes in SCN patients.


CONCLUSIONS
These results suggest that the underlying granulopoietic abnormalities differ between CyN and SCN, and emphasize the presence of additional genetic pathophysiology specific to each disease.
Sera
Yasuhiko
Y
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Kawaguchi
Hiroshi
H
Nakamura
Kazuhiro
K
Sato
Takashi
T
Habara
Masakazu
M
Okada
Satoshi
S
Ishikawa
Nobutsune
N
Kojima
Seiji
S
Katoh
Osamu
O
Kobayashi
Masao
M
D000380:Agranulocytosis / Q000097:blood* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D005091:Exons; D005260:Female; D006801:Humans; D007223:Infant; D019272:Leukocyte Elastase / Q000235:genetics*; D008297:Male; D009154:Mutation; D009503:Neutropenia / Q000097:blood* / Q000145:classification / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*
D017931:DNA Primers; D012697:Serine Endopeptidases; D019272:Leukocyte Elastase; C117309:pancreatic elastase II