Primary immunodeficiency

Primary immunodeficiency (PI) diseases are a group of chronic disorders in which part of the body’s immune system is missing or does not function properly. The immune system’s job is to keep the human body healthy, and free from infections caused by pathogens, including germs, bacteria, and parasites. People with an immunodeficiency cannot protect themselves from these pathogens as well as they should, causing frequent infections that, left untreated, can lead to complications that are hard to cure. WHIM syndrome is a specific PI disease.

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About WHIM Syndrome

What is WHIM Syndrome?

WHIM syndrome is a type of primary immunodeficiency where the body’s immune system does not function properly.


WHIM is an acronym for the characteristic symptoms and some of its laboratory findings: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis.

Warts caused by human papillomavirus (HPV) can be located anywhere on the body, may or may not present in large quantities and often recur despite treatment. It has been reported that, in some cases, warts in the genital area can potentially lead to cancer.

Hypogammaglobulinemia is a reduced level of all infection-fighting antibodies created by your body.

Infections of various types and severity, starting in childhood and often requiring hospitalization. Chronic or repeated bacterial infections can cause other problems. For example, some individuals who experience repeated ear infections may experience hearing loss. Chronic lung infections can lead to a condition called bronchiectasis, which can progress to repeated lung infections and potentially serious complications. Flaws in the immune system cause increased susceptibility to infections and, in some cases, increased risk of cancers.

Myelokathexis is a condition where too many white blood cells are retained in the bone marrow instead of reaching circulation to fight pathogens and infections.


WHIM syndrome is an extremely rare disorder, and its exact prevalence or incidence in the general population is unknown. It can affect both men and women in equal number and may appear in infancy or early childhood. Most individuals with WHIM syndrome are initially diagnosed with one of the more common immune deficiencies or a more common type of neutropenia. The symptoms of WHIM syndrome can vary greatly from one person to another. Some may only have mild symptoms; others may develop potentially life-threatening complications. Because it is a disease with a small number of identified patients, there is a lack of disease awareness in the medical community. For these reasons, health care providers may not always consider WHIM syndrome in their diagnostic process.

What Causes WHIM syndrome?

WHIM syndrome is caused by mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. Genes provide instructions for creating proteins that play critical roles in many functions of the body. When mutation of a gene occurs, the protein product may be faulty, absent, or have increased function. A single protein can affect many organ systems of the body. The mutations that cause WHIM syndrome result in overactive CXCR4 proteins, which result in immunodeficiency.

The mutations in CXCR4 can be inherited from either parent (most cases) or can be the result of a spontaneous new mutation that occurs at conception (more rare).

Symptoms and Diagnosis of WHIM syndrome

In the instances where a diagnosis is made, it is based on the evaluation of clinical signs in addition to:

  • Lab tests for hypogammaglobulinemia and other immune level measurements
  • Biopsy for the presence of myelokathexis
  • Genetic analysis of the CXCR4 gene


The most prevalent symptoms of WHIM syndrome are infections caused by the deficiency of the immune system.

Common infections in children with WHIM syndrome include recurrent middle ear infections (otitis media), infection of the skin and underlying tissue (cellulitis, impetigo, folliculitis, and abscess), bacterial pneumonia, 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 membranes covering the brain (meningitis) have also been reported.

Many WHIM syndrome patients develop widespread HPV-induced warts that are often difficult to treat, generally starting on hands and feet.


Making the diagnosis of WHIM syndrome is very challenging. The order of presentation and severity of symptoms vary from patient to patient. As a result, different medical specialists may be involved in patient care, which makes it difficult to integrate the constellation of symptomology or consider the underlying cause.

The most common lab findings in patient with WHIM syndrome are chronic leukopenia (low white blood cells) and neutropenia, which are the main reasons of the repeated infections reflected in the acronym “WHIM.” Patients are often given the diagnosis of chronic neutropenia or a primary immunodeficiency of unknown origin.

Currently, there is no therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of WHIM syndrome — treatment is directed toward the specific symptoms that are apparent in each individual. Therapy is limited to treatment of acute infections with antibiotics or preventive treatments. Prompt diagnosis and early targeted treatment are important to reduce the frequency or may prevent chronic infections.

Genetic Screening for WHIM Syndrome

WHIM syndrome is caused by several different mutations in the CXCR4 gene and can be identified through a CXCR4 genetic test.

Given the rarity of patients with WHIM syndrome, the Jeffery Modell Foundation and X4 Pharmaceuticals are sponsoring a genetic screening study to better understand the genetics of patients with WHIM syndrome and its prevalence. The objectives of the collaborative study are to establish a systematic diagnostic approach for WHIM syndrome and to support the identification of WHIM syndrome patients by combining clinical features and genetic testing.

The knowledge gained may help patients with WHIM syndrome in the future, as it could help researchers better understand the characteristics of the disease and support earlier diagnosis.

For more information about WHIM syndrome genetic testing, visit WHIM Syndrome Genetic Testing.

“The journey for patients with WHIM syndrome is long and winding, and can take them to numerous pediatric or adult specialists before specific genetic diagnosis and treatment is offered. This study aims to establish a systematic approach for the early diagnosis of WHIM syndrome patients among physicians working in different fields.”

Jolan Walter, MD, Robert A. Good Endowed Chair, Division of Pediatric Allergy & Immunology at the University of South Florida

“WHIM syndrome is one of the primary immunodeficiency diseases which is probably much more common than is currently recognized. Linking clinical presentation and genetic diagnosis will help physicians to care for this underserved patient population.”

David Dale, MD, Professor of Medicine and former Dean of the School of Medicine at the University of Washington

Interested in learning about
X4's clinical study in WHIM syndrome?

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