WHIM syndrome

How does WHIM syndrome present and progress?

Generally, symptoms first appear in early childhood, when most children with WHIM syndrome experience repeated bacterial infections that can be mild or severe, but usually respond promptly to antibiotics. The number and frequency of infections can vary greatly from one child to another. Common infections include recurrent middle ear infections (otitis media), infection of the skin and underlying tissue (cellulitis, impetigo, folliculitis, and abscess), bacterial pneumonia, sinus infection (sinusitis), painful infections of the joints (septic arthritis), dental cavities, and infection of the gums (periodontitis). Bone infection (osteomyelitis), urinary tract infections, and infection of the covering of the brain (meningitis) have also been reported.

Chronic infections can cause additional symptoms. For example, some individuals who experience repeated ear infections may have hearing loss. Repeated episodes of pneumonia may lead to bronchiectasis, the widening of the lung’s airway tubes. Bronchiectasis, in turn, can lead to repeated lung infections and potentially serious complications.

Although neutrophil production occurs normally in the bone marrow of individuals with WHIM syndrome, when these white blood cells mature, they are not released into the bloodstream. This myelokathexis explains why people with WHIM syndrome often have neutropenia even though they have normal numbers of neutrophils in their bone marrow.

Most individuals with WHIM syndrome also have low numbers of B cells, which make antibodies in response to bacterial or viral infection. As a result, affected individuals have hypogammaglobulinemia that leaves them susceptible to infection with specific types of bacteria and, to a lesser extent, certain viruses. Some affected individuals may also have low numbers of other white blood cells, such as T cells or natural killer cells, or of all white blood cells, a condition called panleukopenia or pancytopenia. Not all patients have all of these features.

Patients with WHIM syndrome may develop warts due to infection with HPV, a virus that only infects humans and has more than 150 related types. Warts usually develop during the teen years but can be seen in early childhood. Warts may be widespread, affecting the hands, feet, face, and trunk, and often recur despite treatment. Mucosal, oral, and genital warts may develop and are associated with an increased risk of cancer. Regular monitoring to promptly detect and surgically remove any HPV lesions that appear pre-cancerous or cancerous is recommended.

What treatment options are available?

Treatment of WHIM syndrome may include immunoglobulin replacement therapy, granulocyte colony-stimulating factor (G-CSF), or granulocyte macrophage colony-stimulating factor (GM-CSF), to bolster production and maturation of neutrophils and reduce the incidence of infection.

The use of immunoglobulin replacement therapy has been successful in reducing infections in patients with WHIM syndrome. Immunoglobulin therapy, whether administered intravenously (IVIG) or subcutaneously (SCIG), can treat hypogammaglobulinemia and help reduce the frequency of recurrent bacterial infections. Prompt diagnosis and early aggressive treatment of infections are important to reduce the frequency of chronic bacterial infections. Sometimes, prophylactic antibiotics are useful for preventing infections.

Vaccination against HPV should be strongly considered in patients with WHIM syndrome, given the established safety of the vaccine and the severity of HPV infections in these patients. Periodic revaccination may be necessary, because the underlying immune defects associated with the disorder may lessen the effectiveness of such protection.

A hematopoietic stem cell transplantation (HSCT) using matched umbilical cord blood stem cells was performed in one individual with WHIM syndrome. The individual had a complete resolution of all clinical symptoms without further need for immunoglobulin or G-CSF therapy. HSCT using blood stem cells from another person may be effective, but there are limited studies specifically for WHIM syndrome. 

Because researchers have determined the genetic cause of WHIM syndrome, more targeted treatment is being developed, including two drugs that inhibit the CXCR4 receptor that is overactive in people with WHIM syndrome. Plerixafor is an injectable drug already used for autologous hematopoietic stem cell transplants for some cancers. The National Institutes of Health (NIH) is currently studying plerixafor in comparison to G-CSF in clinical trials. There is also an ongoing phase III clinical trial for a once daily oral drug called mavorixafor. Inhibitors of CXCR4 appear promising, but additional data are needed to confirm preliminary findings of an increase in B cell counts, reduction in infections, and improvement in warts. Research leading to precision therapy is giving many people living with WHIM hope for the future.