WHIM syndrome (or

Wart Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the ...

Hypogammaglobulinemia Hypogammaglobulinemia is a problem with the immune system in which not enough gamma globulins are produced in the blood (thus '' hypo-'' + ''gamma'' + '' globulin'' + '' -emia''). This results in a lower antibody count, which impairs the immune s ...

Immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...

, and

Myelokathexis Myelokathexis is a congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The disorder is believed to be inherited ...

syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...

Pathophysiology

WHIM syndrome results from

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

s in the gene for the

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or Cell signaling, signaling proteins secreted by Cell (biology), cells that induce directional movement of leukocytes, as well as other cell types, including endothelial a ...

receptor,

CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemokin ...

, resulting in a carboxy-terminus truncation of the receptor of between 10 and 19 residues. The gene mutant is located on 2q21. The truncation of the receptor protein results in the inability of downregulation after stimulation. Thus, the receptor remain in an activated state. WHIM syndrome is one of only a few diseases directly and primarily caused by an aberrant chemokine, making its molecular biology important in understanding the role of cell signaling and trafficking. An association with ''

GRK3 G-protein-coupled receptor kinase 3 (GRK3) is an enzyme that in humans is encoded by the ''ADRBK2'' gene. GRK3 was initially called Beta-adrenergic receptor kinase 2 (βARK-2), and is a member of the G protein-coupled receptor kinase subfamily of ...

'' has also been observed.

Diagnosis

Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype

human papilloma virus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...

, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention () of

neutrophils Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying i ...

in the bone marrow (). In addition, lymphocytes and IgG antibody levels (gammaglobulins) are often deficient.

Treatment

Infusions of immune globulin can reduce the frequency of bacterial infections, and

G-CSF Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. Functional ...

GM-CSF Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

therapy improves blood neutrophil counts. As WHIM syndrome is a molecular disease arising from gain-of-function mutations in CXCR4, preclinical studies identified

plerixafor Plerixafor ( INN and USAN, trade name Mozobil) is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients into the bloodstream. The stem cells are then extracted from the blood and transplanted back to the patient. The dr ...

, a specific CXCR4 antagonist, as a potential mechanism-based therapeutic for the disease. Two subsequent clinical trials involving a handful of patients with WHIM syndrome demonstrated that plerixafor could increase white blood cell counts and continues to be a promising targeted therapy. A woman with spontaneous remission of her WHIM syndrome due to

chromothripsis Chromothripsis is a mutational process by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and c ...

in one of her blood stem cells has been identified. In support of these studies, a 2014 phase I clinical trial treated three patients diagnosed with WHIM syndrome with plerixafor twice a day for six months. All three patients presented with multiple reoccurring infections before treatment and all had an increase in their white blood cell count post treatment. One patient (P3) had a decrease in his infections by 40% while the remaining two patients (P1 and P2) had no infections throughout the entirety of the treatment. Plerixafor may also prove to have anti-human papillomavirus (

HPV Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and re ...

) properties as all patients experienced a shrinkage or complete disappearance of their warts. While this treatment shows promise in treating neutropenia (decreased white blood cells), this trial showed no increase of immune globulins in the body. A phase III clinical trial has been approved to compare the infection prevention ability of plerixafor versus the current treatment of

in patients with WHIM.

References

External links

{{Cell surface receptor deficiencies Rare diseases Syndromes affecting immunity Autosomal dominant disorders Noninfectious immunodeficiency-related cutaneous conditions Defects in innate immunity