What is WHIM syndrome?

In this issue of Blood, Kawai and colleagues report careful and detailed studies on the effects of expression of mutant CXCR4 in mobilized human CD 34⁺ cells (peripheral blood progenitor cells or PBSCs) studied in ex vivo cultures and with engraftment into NOD/SCID mice.

WHIM stands for warts, hypogammaglobulinemia, infections, and myelokathexis. In 1964, Wolf Zuelzer¹  first used the term myelokathexis to describe a 10-year-old girl with severe neutropenia who had abundant mature and hypersegmented neutrophils in the bone marrow, but severe peripheral neutropenia. This very interesting patient was also described by Krill et al later that year in the same journal.²  Over the years many similar patients have been reported with varying manifestations, but the hematologic features of lymphocytopenia, neutropenia, and hypersegmented neutrophils in the blood and bone marrow are the common features of all of the well-described cases.

About 5 years ago, it was recognized that the morphologic abnormalities described by Zuelzer in myelokathexis are due to accumulation of apoptotic neutrophils in the marrow and the blood.³  Then, linkage analysis studies and sequencing showed that most cases of this autosomal dominant disorder are due to mutations in CXCR4, the receptor for the important ligand stromal-derived factor-1 (SDF-1).⁴  This receptor-ligand pair is known now to be particularly important in regulating release of neutrophils and their progenitors into the blood from the marrow.⁵ 

These studies show that expression of the mutant CXCR4 transgene is associated with enhanced bone marrow engraftment in the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, increased apoptosis of the transduced cells in the bone marrow, and reduced release of the transduced cells into the blood. These findings are consistent with the name that Zuelzer gave to this disease, myelokathexis, which is derived from “kathexis,” meaning retention. The marrow neutrophils and their precursors are apop-totic because they are trapped in the extravascular spaces of the bone marrow; the cells cannot follow their normal pathway into the circulation.

One of the unique clinical features of myelokathexis and WHIM syndrome is the relative infrequency of severe bacterial infections despite severe chronic neutropenia. These patients have relatively few bacterial infections in contrast to other comparable patients with neutropenia who have congenital or cyclic neutropenia or neutropenia due to myelotoxic drugs. This may be because patients with myelokathexis have an expanded pool of mature neutrophils in the marrow that can mobilize with infections and in response to administration of granulocyte colony-stimulating factor (G-CSF).⁶  Thus, observations of patients with this rare disease show us that it is the marrow neutrophil supply or marrow neutrophil reserve that makes the difference, and the studies by Kawai and colleagues are very useful to help us understand this clinical observation.