WHIM syndrome: congenital immune deficiency disease

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is characterized by susceptibility to human papilloma virus infection-induced warts and carcinomas; neutropenia, B-cell lymphopenia and hypogammaglobulinema-related infections; and bone marrow myelokathexis (myeloid hyperplasia with apoptosis). The purpose of this report is to review new findings about WHIM.

Most WHIM patients have heterozygous C-terminus deletion mutations of the intracellular carboxy terminus of the chemokine receptor CXCR4. WHIM leukocytes have enhanced responses to CXCL12, the cognate ligand of CXCR4. Enhanced activity of CXCR4 delays release of mature neutrophils from bone marrow, resulting in neutropenia and apoptosis of mature neutrophils retained in the marrow. Finding two patients with WHIM who do not have detectable mutations of CXCR4 but whose cells are hyperresponsive to CXCL12 raises the possibility that there is more than one genetic basis for WHIM. One patient had low levels of G-protein receptor kinase 3, and the functional hyperactivity response to CXCL12 was corrected by forced gene transfer-mediated overexpression of G-protein receptor kinase 3, implicating defects in function of this protein as a potential alternate genetic cause of WHIM.

Subjects reviewed include clinical presentation, diagnosis, and treatment of WHIM and advances in understanding the genetic basis of WHIM.