WHIM syndrome

What is WHIM syndrome?

Warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome is an ultra-rare and difficult-to-diagnose primary immunodeficiency (PI) in which the body’s immune system does not function properly, and has trouble fighting infections, especially respiratory, ear, and skin infections. Individuals with WHIM syndrome are more susceptible to life-threatening bacterial infections and to human papillomavirus (HPV) infections, which can cause skin and genital warts and can sometimes lead to cancer. People with WHIM syndrome also have extremely low levels of neutrophils, a type of white blood cell, in their blood. Neutrophils help the body fight off infection, especially bacterial and fungal infections.

People living with WHIM syndrome do not always have the same symptoms, so it can be hard to get the right diagnosis. Some may only have mild symptoms; others may develop potentially life-threatening complications. In fact, most individuals with WHIM syndrome are first misdiagnosed with common variable immune deficiency (CVID) or a more common type of neutropenia. Patients have recurrent infections including pneumonia, sinusitis, and skin infections. The neutropenia-related infections precede the later complications of HPV infections, e.g., warts. Making a correct diagnosis can change the course of treatment and outcomes for those with WHIM syndrome. 

WHIM syndrome is extremely rare, and its exact prevalence is unknown, although it has been estimated at about 1 in 5 million live births. Approximately 60 cases have been reported in the medical literature. It affects both boys and girls in equal numbers, and symptom onset usually occurs in infancy or early childhood. Because of the small number of cases, lack of large clinical studies, and the possibility that other genes influence disease outcomes, healthcare providers do not have a complete picture of symptoms and prognosis.

What causes WHIM syndrome?

In most cases, WHIM syndrome is caused by variants in the CXCR4 gene, which codes for a type of protein called a chemokine receptor. These variants are ‘gain of function,’ which means they increase the activity of the receptor. In WHIM syndrome, the increased activity of CXCR4 prevents mature neutrophils from leaving the bone marrow and entering the bloodstream, and B cell dysfunction, leading to low immunoglobulin levels (hypogammaglobulinemia).

The gene variant that causes WHIM syndrome is inherited as an autosomal dominant trait, where only a single copy of the CXCR4 variant is necessary to cause the disorder. The gene variant can be inherited from either parent or can be the result of a spontaneous change in CXCR4 during the affected individual’s development. The risk of passing the gene variant from affected parent to child is 50% for each pregnancy, regardless of the sex of the resulting child.

Some individuals with the characteristic symptoms of WHIM syndrome do not have a detectable variant in the CXCR4 gene, and their disorder may have other genetic causes.

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 infections (sinusitis), painful infections of the joints (septic arthritis), dental cavities, and infection of the gums (periodontitis). Bone infections (osteomyelitis), urinary tract infections, and infections 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 drugs that inhibit the CXCR4 receptor that is overactive in people with WHIM syndrome. In spring 2024, the U.S. Food and Drug Administration (FDA) approved the CXCR4 antagonist mavorixafor (marketed as Xelremdi by X4 Pharmacueticals) to treat WHIM syndrome.