Congenital neutropenia: an intrinsic cell defect demonstrated by electron microscopy of soft agar colonies

Congenital neutropenia (CN), a disease characterized by recurrent infections leading to death in infancy, shows a maturation arrest of the myeloid series at the promyelocyte-myelocyte level. The potential value of marrow transplantation in this disease would be determined by the nature of the underlying defect. However, studies to date have failed to define whether the defect is intrinsic in the cells or attributable to "environmental" factors. Therefore, marrow of four patients with CN was cultured on soft agar, and the colonies were analyzed by a newly developed ultrastructural method. In parallel, patients' cells were used in feeder layers for normal marrow. Although the patients' colonies appeared grossly normal in size and number, electron microscopy showed only rare neutrophil colonies. These colonies contained markedly aberrant cells exhibiting asynchronous nucleocytoplasmic maturation, convoluted nuclei, excessive cytoplasm, and dearth of granules. Monocyte and eosinophil colonies differentiated normally. Patients' cells and sera supported growth of normal colonies. The studies have demonstrated unequivocally that the neutrophil cell line of patients with CN is intrinsically defective and suggest that attempts at marrow grafting are warranted.