SUMMARY
1. Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome is an autosomal dominant immunodeficiency characterized by low immunoglogulin levels and myelokathexis (the retention of mature neutrophils in the bone marrow). WHIM is caused by heterozygous mutations in the CXC chemokine receptor 4 (CXCR4).
2. CXCL12, the ligand for CXCR4, is expressed by bone marrow stromal cells. Mutant CXCR4 receptors have gain of function properties that results in enhanced leukocyte response to CXCL12 and retention of mature neutrophils in the bone marrow (with resulting peripheral neutropenia).
3. Clinically, patients have increased susceptibility to HPV-induced warts (most often appearing in the second decade of life) and recurrent bacterial sinopulmonary infections characteristic of antibody deficiencies. Patients may also develop skin abscesses and periodontitis due to neutropenia.
4. Laboratory abnormalities include leukopenia primarily due to neutropenia (ANC <500). However, neutrophil function is normal and bone marrow biopsy reveals the presence of mature neutrophils (there is no developmental arrest in myeloid precursors). Low IgG and/or IgA may be present but can also be normal. Some studies have reported rapid loss of antibody titers following vaccination and decreased lymphocyte mitogen/antigen proliferation.
5. The diagnosis of WHIM syndrome is suggested by a history of recurrent warts and sinopulmonary infections with leukopenia, neutropenia, and hypogammaglobulinemia. Identification of mutations in the CXCR4 gene can confirm the diagnosis.
6. Immunoglobulin replacement therapy is effective for reducing bacterial infections in WHIM syndrome. Administration of G-CSF or GM-CSF can result in increased peripheral neutrophils. Warts are typically resistant to local therapy and may require laser ablation.
OVERVIEW
Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome is an autosomal dominant immunodeficiency characterized by low immunoglobulin levels and myelokathexis (the retention of mature neutrophils in the bone marrow). WHIM is caused by heterozygous mutations in the CXC chemokine receptor 4 (CXCR4).
CXCL12, the ligand for CXCR4, is expressed by bone marrow stromal cells. Mutant CXCR4 receptors have gain of function properties that results in enhanced leukocyte response to CXCL12 and retention of mature neutrophils in the bone marrow (with resulting peripheral neutropenia).
Clinically, patients have increased susceptibility to HPV-induced warts (most often appearing in the second decade of life) and recurrent bacterial sinopulmonary infections characteristic of antibody deficiencies. Patients can also develop skin abscesses and periodontitis due to neutropenia.
Laboratory abnormalities include leukopenia primarily due to neutropenia (ANC <500). However, neutrophil function is normal and bone marrow biopsy reveals the presence of mature neutrophils (there is no developmental arrest in myeloid precursors). Low IgG and/or IgA may be present but can also be normal. Some studies have reported rapid loss of antibody titers following vaccination and decreased lymphocyte mitogen/antigen proliferation.
EVALUATION
WHIM syndrome should be considered in patients with a history of recurrent warts, bacterial sinopulmonary infections, and neutropenia.
Step 1: Immune Evaluation
-CBC with Differential
-Quantitative immunoglobulins (IgG, IgM, IgA)
-Antibody titers to vaccine antigens
-Flow cytometry for B cell, T cell, and NK cell enumeration
-T cell proliferation to mitogens
-Leukopenia and neutropenia (ANC <500) may be present on CBC with differential
-Patients can have low quantitative antibody levels of all isotypes
-Protein (Tetanus, Diptheria) and polysaccharide (Pneumococcus) vaccine antibody response should be evaluated. Patients are typically able to mount responses to vaccine antigens but the protective antibodies may be short-lived.
-B cell lymphopenia has been reported in several patients.
-T cell proliferation to mitogens and specific antigens can be reduced in some patients.
Step 2: Additional Evaluation
-Bone Marrow Biopsy
-Unlike congenital neutropenia, WHIM syndrome patients do not have any developmental arrest of myeloid precursors. Bone marrow biopsy typically reveals hypercellularity due to retention of mature neutrophils.
Step 3: Gene Sequencing
-CXCR4 Gene Sequencing
-CXCR4 gene sequencing is currently commercially available (Seattle Children's)
MANAGEMENT
Supportive therapies for immunodeficiency include immunoglobulin therapy. Typical IVIG replacement dosing is started at 400-600mg/kg every 4 weeks. Trough levels should be maintained above 800mg/dl. The total dose or dosing frequency may be increased to achieve desired troughs and clinical response. G-CSF or GM-CSF can result in increased peripheral neutrophil counts. Warts are typically resistant to local therapy and may require laser ablation.
RESOURCES
Literature Resources
1. Kawai 2009
WHIM syndrome (review)
2. Tassone 2009
WHIM syndrome (10 patients)
3. Busillo 2007
Regulation of CXCR4 Signaling