WHIM syndrome has diverse manifestations; some features occur consistently in almost all patients, for example, neutropenia, lymphocytopenia and mild hypogammaglobulinemia. However, the clinical consequences are quite variable across patient cohorts and within families. Each complication is important as a cause for morbidity and a source for patient and family concerns.

BACKGROUND

WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. Although it is very rare, there are more than 100 published case reports [1] since the original reports by Zeulzer et al.[2▪▪] and Krill [3] in 1964. In 2003, Hernandez et al.[4] reported that WHIMs is caused by mutations in CXCR4. Several articles now describe the clinical consequences of these mutations [5, 6, 7▪▪, 8, 9▪, 10, 11▪▪]. The severity of the leukopenia (decreased neutrophils, lymphocytes and monocytes) is a unique feature of this immunodeficiency syndrome. This finding alone should readily lead clinicians to consider this diagnosis. Leukopenia occurs because all types of leukocytes express CXCR4. The CXCR4 mutations cause truncation of the receptor protein, which impairs receptor internalization when leukocytes are exposed to their natural ligand, CXCL12. This chemokine was originally called stromal cell-derived factor-1 (SDS-1)[2▪▪, 12▪▪]. This defect in receptor function results in abnormal retention of leukocytes in bone marrow and at other extravascular sites. The bone marrow shows accumulation of neutrophils at various stages of apoptotic death marked by shrinkage of cells with extremely pyknotic nuclei [2▪▪, 13]. WHIMs is currently of special interest because of the finding that CXCR4 antagonists can increase blood leukocytes and may be an effective therapeutic option for these patients [14–17, 18▪▪].