All About WHIM Syndrome

What is WHIM Syndrome?

WHIM syndrome is a rare genetic primary immunodeficiency disorder in which the body’s immune system cannot function normally and is too weak to fight off infections and other illnesses. Individuals with WHIM syndrome are predisposed to bacterial, fungal, and viral infections, as well as cancer. WHIM syndrome is an acronym that describes the distinctive characteristics of the condition.

‍

Warts

Patients with WHIM syndrome are susceptible to numerous human papillomavirus (HPV) infection induced warts [ x ]. The warts develop on the hands, feet, trunk, and genitals. With a chronic HPV infection, neoplasm of the skin (skin cancer) is a risk.  

‍

Hypogammaglobulinemia

Hypogammaglobulinemia is the term for a decrease in antibodies called immunoglobulins. Immunoglobulins are proteins that help your body recognize and fight off bacteria, viruses, and fungi. 

There are five primary types of immunoglobulins: 

1.) IgG is produced during an initial infection and prevents reinfection, 

2.) IgA provides protection against infection in mucosal areas such as the sinuses, lungs, and gastrointestinal tract, 

3.) IgM is produced as a body’s first response to a new infection, and 

4.) IgE is related to allergies.

5.) IgD comprises only 1 percent of antibodies in the human bloodstream.

IgG is always decreased and IgM is occasionally low in WHIM syndrome patients. 

‍

Infection

With reduced numbers of white blood cells and antibodies that ward off infection, WHIM syndrome patients acquire repeated infections. For example, frequent infections include recurrent upper respiratory infections, ear infections, sinus infections, urinary tract infections, skin infections, infection of the gums, osteomyelitis, septic arthritis, and blood infections. 

‍

Myelokathexis

Myelokathexis is the retention of neutrophils in the bone marrow. Neutrophils are a type of white blood cell produced in the bone marrow. They make up approximately 70 percent of all of the white blood cells in the body. To attack infection, neutrophils leave the marrow to circulate throughout the bloodstream. When myelokathexis occurs, neutrophils are never released into the bloodstream and the cells accumulate in high amounts in the bone marrow. Patients with WHIM syndrome display high levels of neutrophils in the marrow (i.e. hyperplasia) but low levels in circulation. 

‍

Symptoms of WHIM Syndrome

The symptoms of WHIM syndrome are primarily from resulting infections. Aside from various infections, symptoms include:

• Immune deficiency
• Low immunoglobulins
• Decreased specific antibody response to vaccinations
• Warts 
• Persistent human papillomavirus infection (HPV)
• Myelokathexis
• Neutropenia
• Reduction in numbers of all blood cell types (Pancytopenia): Reduced neutrophils, monocytes, B cells, T cells, NK cells, etc. 
• Sore throat 
• Meningitis
• Bronchiectasis (i.e. damaged airways from recurrent respiratory infections) 
• Cavities
• Enlarged lymph nodes
• Folliculitis
• Skin cancer
• Impetigo 
• Cellulitis
• Cutaneous abscess
• Hearing impairment (i.e. from repeated ear infections) 

‍

Causes of WHIM Syndrome

Most cases of WHIM syndrome are caused by mutations in the CXCR4 gene. Typically, the CXCR4 gene is responsible for making a receptor that provides instructions for cells to travel to various locations in the body and when to stop. In WHIM syndrome, the mutations are known as  gain-of-function mutations because the protein becomes hyperfunctional. Cell trafficking increases.

‍

How Rare is WHIM Syndrome?

Few individuals harbor CXCR4 mutations associated with WHIM syndrome. There are an estimated 100 confirmed cases worldwide. Experts expect the disorder is more prevalent than current medical literature suggests and many patients go undiagnosed or misdiagnosed with another immunodeficiency. 

WHIM syndrome has an autosomal dominant inheritance pattern. A single copy of the disease-associated mutation causes the disease.

‍

Diagnosing WHIM Syndrome

Genetic sequencing is the only true confirmation of WHIM syndrome, but the following tests are used in the diagnostic process after a thorough evaluation: 

• A complete blood count is a blood test that measures the basic blood cells. It will show low neutrophil counts, which is indicative of neutropenia, in those with WHIM syndrome.
• Testing quantitative immunoglobulins is also significant. 
• Specific antibody titers for tetanus, diphtheria, and more are consistent with a decreased specific antibody response to vaccination. Patients with compromised immune systems do not maintain appropriate levels of antibodies from past vaccines and viral illnesses. 
• A lymphocyte enumeration tests for the percentage and cell count of lymphocytes in the blood. Lymphocytes are a type of white blood cell that fight bacteria and viruses. There are three types: T cells, B cells, and NK cells. WHIM syndrome patients have lymphopenia or low amounts of B cells. Sometimes T cells and NK cells are low too. 

A bone marrow biopsy will detect myelokathexis, one of the hallmark characteristics of WHIM syndrome.

‍

WHIM Syndrome Treatment

There is no cure for WHIM syndrome. Its treatment revolves around symptom management. 

• The most common form of treatment is intravenous immunoglobulin or IVIG. IVIG replaces the patient’s deficient antibodies with the healthy antibodies from thousands of blood donors. This is prescribed monthly through an infusion and helps prevent infections. 
• Additionally, patients benefit from therapies that encourage neutrophil production such as Granulocyte Colony Stimulating Factor (G-CSF) or Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF). 
• Because the Human papillomavirus (HPV) may lead to cancer, the HPV vaccination is administered preventatively to reduce the risk. To ensure the vaccine remains effective, patients must be re-vaccinated as they begin to lose their antibodies over time. 
• Bone marrow transplantation is experimental in WHIM syndrome. After undergoing rigorous chemotherapy, the patient’s immune system is completely eradicated and replaced with a donor’s immune system through the collection of stem cells. 

‍

WHIM Syndrome Prognosis

WHIM syndrome patients are at a higher risk for fatal complications from recurrent infections. However, life expectancy with the disorder can exceed mid-adulthood. Prognosis depends on the severity of symptoms and whether or not the individual develops cancer from chronic HPV infection.

Photo Source: Photo by Ketut Subiyanto from Pexels