Genetic causes of congenital neutropenia. Neutrophilic granulopoiesis occurs primarily in the bone marrow through the stepwise maturation of myeloid progenitors (eg, colony-forming unit–granulocyte, monocyte, or CFU-GM) to promyelocytes (pro), myelocytes, and finally mature neutrophils (PMNs). PMNs are then released into the blood in a regulated fashion. Gene mutations associated with SCN are shown in the left panel. These mutations are typically associated with isolated severe neutropenia and a block in granulocytic differentiation. In contrast, mutations of CXCR4 and CXCR2 cause neutropenia by inhibiting neutrophil release from the bone marrow. Stepensky et al describe a new syndrome characterized by neutropenia, myelofibrosis, and impaired protein trafficking to endosomes that is due to VPS45 mutations. Mutations of VPS45 can be added to the list of gene mutations that affect protein trafficking to endosomes and are associated with congenital neutropenia (middle panel). Professional illustration by Marie Dauenheimer.