Congenital neutropenia: impaired maturation with diminished stem-cell input

Children with congenital neutropenia (Kostman disease) present a syndrome of recurrent and eventually fatal bacterial infections. The disease is uniformly lethal and the mean age at death is 24 months. To attempt to better understand the nature of this inborn error, we have studied marrow and peripheral blood of 3 children with the disease. Along with classic morphologic analysis we have used the technic of soft agar bone marrow culture in vitro. All 3 patients showed marked deficiency of numbers of neutrophils in the peripheral blood, intermittent monocytosis especially with infection, and predominant nitroblue tetrazolium (NBT) dye staining in monocytes during infection. The marrow of all 3 patients showed evidence of maturation arrest at the promyelocyte stage and very few or no neutrophils. Two cases showed no neutrophils in the Rebuck skin window inflammatory study. The 3rd case, however, developed small numbers of neutrophils in the peripheral blood, up to 6%, but the first 2 patients, although studied on many occasions, did not show neutrophils above 1%. Evidence from soft agar culture of bone marrow in 1 patient was compatible with the view that development of committed neutrophil stem cells is defective. This patient did not develop neutrophils in soft agar culture and showed loose colonies developing only to promyelocytes. In the 2nd case, where depression of neutrophil development was somewhat less severe clinically, culture of the marrow in soft agar yielded normal neutrophil colonies and none of the loose colonies showing arrested maturation were seen. These findings suggest that the basic mechanism underlying the congenital neutropenias may differ from patient to patient.