CXCR4 and WHIM syndrome: At the molecular level, WHIM syndrome is caused by heterozygous gain-of-function mutations at the C-terminal end of CXCR4 that affect key residues involved in receptor phosphorylation and desensitization (64), explaining the associated hyperactivation of downstream signaling and the retention of leukocytes in the BM, causing robust neutropenia (65).