21 INTRODUCTION: WHIM syndrome is a rare combined primary immunodeficiency 
disorder caused by autosomal dominant gain-of-function mutations in the 
chemokine receptor CXCR4. It is the only Mendelian condition known to be caused 
by mutation of a chemokine or chemokine receptor. As such, it provides a 
scientific opportunity to understand chemokine-dependent immunoregulation in 
humans and a medical opportunity to develop mechanism-based treatment and cure 
strategies.
22 AREAS COVERED: This review covers the clinical features, genetics, 
immunopathogenesis and clinical management of WHIM syndrome. Clinical trials of 
targeted therapeutic agents and potential cure strategies are also included.
23 EXPERT OPINION: WHIM syndrome may be particularly amenable to mechanism-based 
therapeutics for three reasons: 1) CXCR4 has been validated as the molecular 
target in the disease by Mendelian genetics; 2) the biochemical abnormality is 
excessive CXCR4 signaling; and 3) antagonists selective for CXCR4 have been 
developed. Plerixafor is FDA-approved for hematopoietic stem cell (HSC) 
mobilization and has shown preliminary safety and efficacy in phase I clinical 
trials in WHIM syndrome. Gene editing may represent a viable cure strategy, 
since chromothriptic deletion of the disease allele in HSCs resulted in clinical 
cure of a patient and because CXCR4 haploinsufficiency enhances engraftment of 
transplanted HSCs in mice.