Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare genetic disease of the immune system. Its name is an acronym for its main clinical manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis. Hypogammaglobulinemia is a deficiency in specific infection-fighting antibodies in the blood. Myelokathexis refers to the failure of neutrophils — infection-fighting white blood cells — to move from the bone marrow into the bloodstream where they can patrol the body. WHIM syndrome patients also have trouble distributing most other types of immune cells to the blood. Such defects in the immune system predispose WHIM syndrome patients to frequent bacterial and viral infections, persistent skin and genital warts, and an increased risk of developing cancer caused by human papillomavirus.
In 2003, researchers at Mount Sinai School of Medicine in New York discovered that WHIM syndrome is caused by mutations in the CXC chemokine receptor 4 (CXCR4) gene. One of the many functions of CXCR4 is to tether white blood cells to the bone marrow until they are mature enough to be released into the blood. WHIM mutations result in excessive CXCR4 receptor activity, which traps the cells inside the bone marrow and prevents their movement into the bloodstream and the rest of the body.
Standard therapy for WHIM syndrome aims to restore deficient blood components. It involves intravenous immunoglobulin, a blood product containing antibodies, or granulocyte colony-stimulating factor (G-CSF), an immune-cell-growth molecule. However, these treatments do not specifically target the CXCR4 genetic defect, and their long-term efficacy has not been established through clinical trials.
In 2011, NIAID investigators tested the drug plerixafor in WHIM syndrome patients over the course of one week to investigate safety and to establish the minimally effective dose for raising the number of neutrophils in the blood to a level at which infections would be unlikely to occur. Plerixafor, which blocks the activity of CXCR4, is approved by the Food and Drug Administration (FDA) to mobilize blood-forming stem cells from the bone marrow for collection and eventual transplantation after cancer therapy. Because it can free immune cells to move into the blood in healthy people and specifically targets CXCR4, it was considered an ideal drug candidate for treating patients with WHIM syndrome. In this study, the drug was safe and could elevate neutrophils to a safe level using approximately 5 percent of the FDA-approved dose for stem cell mobilization.
Subsequently, a 2014 study by NIAID researchers revealed that low-dose plerixafor, designed to reduce but not eliminate CXCR4 activity, was safe and effective at raising the neutrophil count in the blood over the course of 6 months. The study also provided preliminary evidence of efficacy at reducing wart burden and the incidence of infection. The scientists then demonstrated in 2019 that treating three people with WHIM syndrome with low-dose plerixafor for 19 to 52 months safely reduced or eliminated symptoms and markedly improved quality of life. NIAID researchers are now comparing the safety and efficacy of plerixafor to that of G-CSF for the treatment of WHIM syndrome in a clinical trial that will end in 2020.
Interestingly, in 2015 NIAID researchers reported the spontaneous cure of a person with WHIM syndrome that resulted from a genetic phenomenon called chromothripsis, or “chromosome shattering,” which caused a random and fortuitous deletion of the mutant CXCR4 gene. Evidently, a hematopoietic stem cell lacking mutant CXCR4 survived and repopulated all of the person’s neutrophils. The NIAID team is exploring how to apply the study findings to improve bone marrow transplantation, which relies on the ability of donor stem cells to repopulate in a recipient.