The pathogenesis of neutropenia in WHIM syndrome. WHIM syndrome is characterized by neutropenia, lymphopenia, and monocytopenia despite hypercellular bone marrow (myelokathexis). The disease is caused by heterozygous mutations of CXCR4 resulting in a carboxy-terminus truncation of the receptor. Because of the peptide truncation, the receptor becomes hyperresponsive to the ligand CXCL12, resulting in the accumulation of mature neutrophils in the bone marrow. The treatment with granulocyte colony-stimulating factor (G-CSF) results in the downregulation of CXCR4 and a decreased cell responsiveness to CXCL12, promoting neutrophil mobilization from the bone marrow to the peripheral blood.